Cancers

8 pages, 526 KiB

Open AccessArticle

A Comparison of Skin Staining after Sentinel Lymph Node Biopsy in Women Undergoing Breast Cancer Surgery Using Blue Dye and Superparamagnetic Iron Oxide Nanoparticle (SPIO) Tracers

by Allan Jazrawi, Madeleine Wärnberg, Abdi-Fatah Hersi, Christine Obondo, Lida Pistioli, Staffan Eriksson, Andreas Karakatsanis and Fredrik Wärnberg

Cancers 2022, 14(23), 6017; https://doi.org/10.3390/cancers14236017 - 6 Dec 2022

Cited by 7 | Viewed by 2182

Abstract

Superparamagnetic iron oxide nanoparticles (SPIO) are a tracer for sentinel lymph node (SLN) detection. In a preplanned secondary analysis of a prospective clinical trial (SentiDose) we reported on skin staining after SPIO and blue dye (BD) injections. For SPIO, either a 1.5 mL [...] Read more.

Superparamagnetic iron oxide nanoparticles (SPIO) are a tracer for sentinel lymph node (SLN) detection. In a preplanned secondary analysis of a prospective clinical trial (SentiDose) we reported on skin staining after SPIO and blue dye (BD) injections. For SPIO, either a 1.5 mL retroareolar injection on the day of surgery or a 1.0 mL peritumoral/retroareolar injection 1–7 days before surgery was given. A 1.0 mL sub-/intradermal periareolar injection of BD was also administered to all these women. Staining was then assessed at 6, 12 and 24 months after surgery. A total of 270 women received SPIO and were operated on with breast-conserving surgery. Of these, 204 women also received BD. A total of 58 (21.5%) women had an SPIO stain 6 months postoperatively with a median size of 6.8 cm² (p = 0.56), while 51 (25.0%) had a BD stain with a median size of 8.5 cm² (p = 0.93). The incidence and size of SPIO and BD staining decreased over time reciprocally. At 24 months, the incidence and median size of SPIO was 23 (8.6%) and 4 cm², respectively. For BD, the incidence was 14 (6.3%, p = 0.13), and the median size was 3.5 cm² (p = 0.18). There was, therefore, no statistically significant difference in the incidence or size of skin staining between SPIO and BD over time. Full article

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12 pages, 564 KiB

Open AccessArticle

Early Referral for Breast-Cancer-Related Lymphedema: Do We Follow the Evidence? A Two-Year Prospective Multicenter Cohort Study

by Ad A. Hendrickx, Saskia W. Küthe, Cees P. van der Schans, Wim P. Krijnen, Chantal M. Mouës-Vink and Robert J. Damstra

Cancers 2022, 14(23), 6016; https://doi.org/10.3390/cancers14236016 - 6 Dec 2022

Cited by 1 | Viewed by 1873

Abstract

The early detection of breast-cancer-related lymphedema and referral for therapy has the potential to reduce lymphedema-related morbidity. Although research shows the benefits, a gap is observed between evidence and daily practice. We aimed to determine whether the early detection of lymphedema and referral [...] Read more.

The early detection of breast-cancer-related lymphedema and referral for therapy has the potential to reduce lymphedema-related morbidity. Although research shows the benefits, a gap is observed between evidence and daily practice. We aimed to determine whether the early detection of lymphedema and referral for treatment is adequate following the current guidelines. Women with primary breast cancer treated with breast-conserving therapy or ablative treatment were included. Demographic-, general health-, tumor-, and treatment-related data were recorded. Bilateral arm volume measurements were performed preoperatively and 3, 6, 12, and 24 months post-surgery. A 5% or greater Relative Volume Change was considered the cutoff point for lymphedema and as an indication for therapy referral. After 24 months post-surgery, the main outcomes show that among the patients with early signs of lymphedema, based on a Relative Volume Change ≥5%, a nonreferral for therapy was noted in 83%. Additionally, we observed a significant improvement of the mean Relative Volume Change at 24 months within this group, which might implicate that nonreferral was an adequate choice and that watchful waiting is appropriate when lymphedema is detected within the first year post-surgery. Full article

(This article belongs to the Special Issue New Insights in Lymphedema after Cancer to Enhance Clinical Practice)

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18 pages, 434 KiB

Open AccessArticle

Breast Cancer Detection Using Convoluted Features and Ensemble Machine Learning Algorithm

by Muhammad Umer, Mahum Naveed, Fadwa Alrowais, Abid Ishaq, Abdullah Al Hejaili, Shtwai Alsubai, Ala’ Abdulmajid Eshmawi, Abdullah Mohamed and Imran Ashraf

Cancers 2022, 14(23), 6015; https://doi.org/10.3390/cancers14236015 - 6 Dec 2022

Cited by 24 | Viewed by 3025

Abstract

Breast cancer is a common cause of female mortality in developing countries. Screening and early diagnosis can play an important role in the prevention and treatment of these cancers. This study proposes an ensemble learning-based voting classifier that combines the logistic regression and [...] Read more.

Breast cancer is a common cause of female mortality in developing countries. Screening and early diagnosis can play an important role in the prevention and treatment of these cancers. This study proposes an ensemble learning-based voting classifier that combines the logistic regression and stochastic gradient descent classifier with deep convoluted features for the accurate detection of cancerous patients. Deep convoluted features are extracted from the microscopic features and fed to the ensemble voting classifier. This idea provides an optimized framework that accurately classifies malignant and benign tumors with improved accuracy. Results obtained using the voting classifier with convoluted features demonstrate that the highest classification accuracy of 100% is achieved. The proposed approach revealed the accuracy enhancement in comparison with the state-of-the-art approaches. Full article

(This article belongs to the Special Issue Application of Novel Technologies in the Early Detection of Gynaecological Cancers)

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22 pages, 3182 KiB

Open AccessArticle

Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells

by Ipek Bulut, Adam Lee, Buse Cevatemre, Dusan Ruzic, Roman Belle, Akane Kawamura, Sheraz Gul, Katarina Nikolic, A. Ganesan and Ceyda Acilan

Cancers 2022, 14(23), 6014; https://doi.org/10.3390/cancers14236014 - 6 Dec 2022

Cited by 15 | Viewed by 3009

Abstract

Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC₅₀ values of 540, 110, and 290 nM, [...] Read more.

Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC₅₀ values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC₅₀ values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated. Full article

(This article belongs to the Special Issue Recent Developments of Histone Deacetylase Inhibitors as Anticancer Agents)

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14 pages, 1101 KiB

Open AccessArticle

Clinical Potential of Circulating Cell-Free DNA (cfDNA) for Longitudinally Monitoring Clinical Outcomes in the First-Line Setting of Non-Small-Cell Lung Cancer (NSCLC): A Real-World Prospective Study

by Valerio Gristina, Nadia Barraco, Maria La Mantia, Luisa Castellana, Lavinia Insalaco, Marco Bono, Alessandro Perez, Delia Sardo, Sara Inguglia, Federica Iacono, Sofia Cutaia, Tancredi Didier Bazan Russo, Edoardo Francini, Lorena Incorvaia, Giuseppe Badalamenti, Antonio Russo, Antonio Galvano and Viviana Bazan

Cancers 2022, 14(23), 6013; https://doi.org/10.3390/cancers14236013 - 6 Dec 2022

Cited by 20 | Viewed by 2302

Abstract

Background: Despite the increasing implementation of targeted and immunotherapy-based treatments, the prognosis of patients with advanced NSCLC remains dismal. We prospectively evaluated longitudinal plasma cfDNA kinetics as an early marker of therapeutic efficacy in patients with advanced NSCLC undergoing standard first-line treatments. Methods: [...] Read more.

Background: Despite the increasing implementation of targeted and immunotherapy-based treatments, the prognosis of patients with advanced NSCLC remains dismal. We prospectively evaluated longitudinal plasma cfDNA kinetics as an early marker of therapeutic efficacy in patients with advanced NSCLC undergoing standard first-line treatments. Methods: From February 2020 to May 2022, treatment-naïve patients with advanced NSCLC were consecutively enrolled at the Medical Oncology Unit of the Paolo Giaccone University Hospital, Palermo (Italy). We quantified cfDNA in terms of ng/μL using a Qubit^TM dsDNA HS Assay Kit. The agreement between the cfDNA and radiologic response was evaluated from baseline (T0) to the radiologic evaluation (T1). Results: A total of 315 liquid biopsy samples were collected from 63 patients at baseline, with a total of 235 paired plasma samples from 47 patients at disease re-evaluation. A fair concordance was observed between early and durable radiographic and cfDNA response (Cohen’s kappa coefficient = 0.001); 11 and 18 patients receiving TKI (Pearson’s chi-squared test = 4.278; Cohen’s kappa coefficient = 0.039) and IO treatments (Pearson’s chi-squared test = 7.481; Cohen’s kappa coefficient = 0.006) showed a significant and durable association between cfDNA dynamics and the first radiologic evaluation, whereas among the 18 patients undergoing CT, no significant correlation was observed (Pearson’s chi-squared test = 0.720; Cohen’s kappa coefficient = 0.396). The ECOG-PS 2 patients presented with the mean baseline cfDNA levels 2.6-fold higher than those with ECOG-PS 0–1 (1.71 vs. 0.65 ng/µL; p = 0.105). Conclusions: Our real-world study demonstrates that quantitative changes in cfDNA values correlated with responses to therapy and relapse of disease in treatment-naïve patients with advanced NSCLC undergoing TKI- and IO-based treatments. Full article

(This article belongs to the Special Issue Cell-Free DNA as Prognostic and Predictive Biomarker in Solid Cancers)

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14 pages, 1665 KiB

Open AccessArticle

Metabolic-Associated Fatty Liver Disease, Hepatitis B Surface Antigen Seroclearance, and Long-Term Risk of Hepatocellular Carcinoma in Chronic Hepatitis B

by Ming-Whei Yu, Chih-Lin Lin, Chun-Jen Liu, Wan-Jung Wu, Jui-Ting Hu and Yi-Wen Huang

Cancers 2022, 14(23), 6012; https://doi.org/10.3390/cancers14236012 - 6 Dec 2022

Cited by 9 | Viewed by 1943

Abstract

The value of metabolic-associated fatty liver disease (MAFLD) and its ability to assess hepatocellular carcinoma (HCC) risk remains uncertain for chronic hepatitis B (CHB). We evaluated the impacts of MAFLD and its coincidental metabolic abnormalities and related genetic predisposition on HCC incidence and [...] Read more.

The value of metabolic-associated fatty liver disease (MAFLD) and its ability to assess hepatocellular carcinoma (HCC) risk remains uncertain for chronic hepatitis B (CHB). We evaluated the impacts of MAFLD and its coincidental metabolic abnormalities and related genetic predisposition on HCC incidence and mortality outcomes in CHB. We analyzed data from 1453 HBsAg-positive men (median age = 49.2 years at baseline) from a cohort of civil servants recruited from 1989–1992. MAFLD was defined as hepatic steatosis on ultrasound with obesity, diabetes, or metabolic dysfunction at baseline. During follow-up (median = 19.3 years), 105 HCC events occurred. MAFLD was not associated with HCC (adjusted hazard ratio (aHR) = 1.02) but was associated with a higher HBsAg seroclearance rate (aHR = 1.43). In mediation analysis, HBsAg seroclearance driven by hepatic steatosis explained 31.6% of the association between MAFLD and HCC. Antiviral treatment or fatty liver disease-associated genetic variants did not influence the MAFLD–HCC association. In contrast, even after adjustment for MAFLD and the other metabolic abnormalities, diabetes (aHR = 2.28), obesity (aHR = 1.72), and metabolic dysfunction (aHR = 3.30) increased the risk of HCC (all p < 0.030). The risk of HCC increased with the number of metabolic abnormalities (vs 0: aHR = 2.05 and 5.72 for 2 and ≥ 3 metabolic abnormalities, respectively), and the cumulative effect of metabolic abnormalities was found across subgroups categorized by hepatic steatosis as well as in participants both with and without HBsAg seroclearance. In conclusion, MAFLD was not associated with increased HCC incidence in CHB. A more informative assessment of HCC risk can be obtained by taking into account the number of metabolic abnormalities. Full article

(This article belongs to the Section Infectious Agents and Cancer)

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10 pages, 945 KiB

Open AccessArticle

Analysis of the Risk of Oral Squamous Cell Carcinoma in Patients with and without Recurrent Aphthous Stomatitis: A Retrospective Evaluation of Real-World Data of about 150,000 Patients

by Moritz Hertel, Senem Birinci, Max Heiland, Robert Preissner, Susanne Nahles, Andrea-Maria Schmidt-Westhausen and Saskia Preissner

Cancers 2022, 14(23), 6011; https://doi.org/10.3390/cancers14236011 - 6 Dec 2022

Cited by 2 | Viewed by 2148

Abstract

Background: Recurrent aphthous stomatitis (RAS) is found among the most frequent diseases of the oral cavity. It is characterized by repeated formation of painful ulcers. The question has risen if due to potential tumor-promoting inflammation and sustaining proliferative signaling RAS may contribute to [...] Read more.

Background: Recurrent aphthous stomatitis (RAS) is found among the most frequent diseases of the oral cavity. It is characterized by repeated formation of painful ulcers. The question has risen if due to potential tumor-promoting inflammation and sustaining proliferative signaling RAS may contribute to oral cancer. Accordingly, the aim of the study was to assess if an association of RAS and the development oral squamous cell carcinoma (OSCC) could be found in a larger cohort. As recurrent aphthous stomatitis is not classified as an oral potentially malignant disorder, it was assumed that the risk of OSCC did not differ between patients with (cohort I) and without RAS (cohort II). Methods: Retrospective clinical data of patients diagnosed with and without RAS (International Classification of Diseases (ICD)-10 code K12) within the past 20 years and a body mass index of 19–30 kg/m² were retrieved from the TriNetX database to gain initial cohort 0. Subjects suffering from RAS were assigned to cohort I, whereby cohort II was obtained from the remaining individuals, and by matching for age, gender, as well as (history of) nicotine and alcohol dependence. After defining the primary outcome as “OSCC” (ICD-10 codes C00-C14), a Kaplan–Meier analysis was performed, and risk and odds ratios were calculated. Results: Of a total of 24,550,479 individuals in cohort 0, 72,845 subjects were each assigned to cohort I (females: 44,031 (60.44%); males: 28,814 (39.56%); mean current age (±standard deviation) = 35.51 ± 23.55 years) and II (females: 44,032 (60.45%); males: 28,813 (39.55%); mean current age (±standard deviation) = 35.51 ± 23.56 years). Among the cohorts I and II, 470 and 135 patients were diagnosed with OSCC within five years. The according risk of developing oral cancer was 0.65% and 0.18%, whereby the risk difference of 0.47% was highly significant (p < 0.0001; Log-Rank test). The RR and OR were calculated as 3.48 (95% confidence interval (CI) lower: 2.88 and upper: 4.21) and 3.50 (95% CI lower: 2.89 and upper: 4.24). Conclusions: Among the patients suffering from RAS, a significantly augmented risk of developing OSCC was found. However, it has to be emphasized that the recent literature does not provide any confirmatory evidence that supports the retrieved results. Furthermore, the findings need to be interpreted cautiously due to specific limitations that come along with the applied methods. It should thus far only be concluded that further research is necessary to evaluate hypotheses that may be retrieved from the obtained results. Despite this controversy, oral ulcers suspicious of OSCC should undergo biopsy. Trial Registration: Due to the retrospective nature of the study, no registration was necessary. Full article

(This article belongs to the Special Issue Bioinformatics in Cancer Diagnostics and Screening)

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22 pages, 2948 KiB

Open AccessReview

Cytoreductive Surgery (CRS) and HIPEC for Advanced Ovarian Cancer with Peritoneal Metastases: Italian PSM Oncoteam Evidence and Study Purposes

by Daniele Marrelli, Luca Ansaloni, Orietta Federici, Salvatore Asero, Ludovico Carbone, Luigi Marano, Gianluca Baiocchi, Marco Vaira, Federico Coccolini, Andrea Di Giorgio, Massimo Framarini, Roberta Gelmini, Carmen Palopoli, Fabio Accarpio and Anna Fagotti

Cancers 2022, 14(23), 6010; https://doi.org/10.3390/cancers14236010 - 6 Dec 2022

Cited by 5 | Viewed by 2797

Abstract

Ovarian cancer is the eighth most common neoplasm in women with a high mortality rate mainly due to a marked propensity for peritoneal spread directly at diagnosis, as well as tumor recurrence after radical surgical treatment. Treatments for peritoneal metastases have to be [...] Read more.

Ovarian cancer is the eighth most common neoplasm in women with a high mortality rate mainly due to a marked propensity for peritoneal spread directly at diagnosis, as well as tumor recurrence after radical surgical treatment. Treatments for peritoneal metastases have to be designed from a patient’s perspective and focus on meaningful measures of benefit. Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery with regional chemotherapy, has been proposed to treat advanced ovarian cancer. Preliminary results to date have shown promising results, with improved survival outcomes and tumor regression. As knowledge about the disease process increases, practice guidelines will continue to evolve. In this review, we have reported a broad overview of advanced ovarian cancer management, and an update of the current evidence. The future perspectives of the Italian Society of Surgical Oncology (SICO) are discussed conclusively. Full article

(This article belongs to the Special Issue Peritoneal Surface Malignancies (PSM): The SICO (Italian Society of Surgical Oncology) PSM—Oncoteam Experience, Result Analysis, and Studies’ Purpose)

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39 pages, 8167 KiB

Open AccessEditor’s ChoiceArticle

Integrating Pharmacogenomics Data-Driven Computational Drug Prediction with Single-Cell RNAseq to Demonstrate the Efficacy of a NAMPT Inhibitor against Aggressive, Taxane-Resistant, and Stem-like Cells in Lethal Prostate Cancer

by Suman Mazumder, Taraswi Mitra Ghosh, Ujjal K. Mukherjee, Sayak Chakravarti, Farshad Amiri, Razan S. Waliagha, Farnaz Hemmati, Panagiotis Mistriotis, Salsabil Ahmed, Isra Elhussin, Ahmad-Bin Salam, Windy Dean-Colomb, Clayton Yates, Robert D. Arnold and Amit K. Mitra

Cancers 2022, 14(23), 6009; https://doi.org/10.3390/cancers14236009 - 6 Dec 2022

Cited by 8 | Viewed by 4385

Abstract

Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) [...] Read more.

Metastatic prostate cancer/PCa is the second leading cause of cancer deaths in US men. Most early-stage PCa are dependent on overexpression of the androgen receptor (AR) and, therefore, androgen deprivation therapies/ADT-sensitive. However, eventual resistance to standard medical castration (AR-inhibitors) and secondary chemotherapies (taxanes) is nearly universal. Further, the presence of cancer stem-like cells (EMT/epithelial-to-mesenchymal transdifferentiation) and neuroendocrine PCa (NEPC) subtypes significantly contribute to aggressive/lethal/advanced variants of PCa (AVPC). In this study, we introduced a pharmacogenomics data-driven optimization-regularization-based computational prediction algorithm (“secDrugs”) to predict novel drugs against lethal PCa. Integrating secDrug with single-cell RNA-sequencing/scRNAseq as a ‘Double-Hit’ drug screening tool, we demonstrated that single-cells representing drug-resistant and stem-cell-like cells showed high expression of the NAMPT pathway genes, indicating potential efficacy of the secDrug FK866 which targets NAMPT. Next, using several cell-based assays, we showed substantial impact of FK866 on clinically advanced PCa as a single agent and in combination with taxanes or AR-inhibitors. Bulk-RNAseq and scRNAseq revealed that, in addition to NAMPT inhibition, FK866 regulates tumor metastasis, cell migration, invasion, DNA repair machinery, redox homeostasis, autophagy, as well as cancer stemness–related genes, HES1 and CD44. Further, we combined a microfluidic chip-based cell migration assay with a traditional cell migration/‘scratch’ assay and demonstrated that FK866 reduces cancer cell invasion and motility, indicating abrogation of metastasis. Finally, using PCa patient datasets, we showed that FK866 is potentially capable of reversing the expression of several genes associated with biochemical recurrence, including IFITM3 and LTB4R. Thus, using FK866 as a proof-of-concept candidate for drug repurposing, we introduced a novel, universally applicable preclinical drug development pipeline to circumvent subclonal aggressiveness, drug resistance, and stemness in lethal PCa. Full article

(This article belongs to the Collection Prostate Cancer: Pathophysiology, Pathology and Therapy)

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11 pages, 1917 KiB

Open AccessArticle

Small Gastric Stromal Tumors: An Underestimated Risk

by Jintao Guo, Qichao Ge, Fan Yang, Sheng Wang, Nan Ge, Xiang Liu, Jing Shi, Pietro Fusaroli, Yang Liu and Siyu Sun

Cancers 2022, 14(23), 6008; https://doi.org/10.3390/cancers14236008 - 6 Dec 2022

Cited by 4 | Viewed by 1925

Abstract

Background and Objectives: Small gastrointestinal stromal tumors (GISTs) are defined as tumors less than 2 cm in diameter, which are often found incidentally during gastroscopy. There is controversy regarding the management of small GISTs, and a certain percentage of small GISTs become malignant [...] Read more.

Background and Objectives: Small gastrointestinal stromal tumors (GISTs) are defined as tumors less than 2 cm in diameter, which are often found incidentally during gastroscopy. There is controversy regarding the management of small GISTs, and a certain percentage of small GISTs become malignant during follow-up. Previous studies which used Sanger targeted sequencing have shown that the mutation rate of small GISTs is significantly lower than that of large tumors. The aim of this study was to investigate the overall mutational profile of small GISTs, including those of wild-type tumors, using whole-exome sequencing (WES) and Sanger sequencing. Methods: Thirty-six paired small GIST specimens, which were resected by endoscopy, were analyzed by WES. Somatic mutations identified by WES were confirmed by Sanger sequencing. Sanger sequencing was performed in an additional 38 small gastric stromal tumor samples for examining hotspot mutations in KIT, PDGFRA, and BRAF. Results: Somatic C-KIT/PDGFRA mutations accounted for 81% of the mutations, including three novel mutation sites in C-KIT at exon 11, across the entire small gastric stromal tumor cohort (n = 74). In addition, 15% of small GISTs harbored previously undescribed BRAF-V600E hotspot mutations. No significant correlation was observed among the genotype, pathological features, and clinical classification. Conclusions: Our data revealed a high overall mutation rate (~96%) in small GISTs, indicating that genetic alterations are common events in early GIST generation. We also identified a high frequency of oncogenic BRAF-V600E mutations (15%) in small GISTs, which has not been previously reported. Full article

(This article belongs to the Topic Soft Tissue Sarcomas: Treatment and Management)

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17 pages, 742 KiB

Open AccessSystematic Review

The Reporting, Use, and Validity of Patient-Reported Outcomes in Multiple Myeloma in Clinical Trials: A Systematic Literature Review

by Sam Salek, Tatiana Ionova, Esther Natalie Oliva, Marike Andreas, Nicole Skoetz, Nina Kreuzberger and Edward Laane

Cancers 2022, 14(23), 6007; https://doi.org/10.3390/cancers14236007 - 6 Dec 2022

Cited by 5 | Viewed by 2203

Abstract

Background: Patient-reported outcomes (PROs) are becoming increasingly important in supporting clinical outcomes in clinical trials. In multiple myeloma (MM), PRO measurement is useful to reveal how treatment affects physical, psychosocial, and functional behaviour as well as symptoms and treatment-related adverse events to evaluate [...] Read more.

Background: Patient-reported outcomes (PROs) are becoming increasingly important in supporting clinical outcomes in clinical trials. In multiple myeloma (MM), PRO measurement is useful to reveal how treatment affects physical, psychosocial, and functional behaviour as well as symptoms and treatment-related adverse events to evaluate the benefit-risk ratio of a particular drug or drug combination. We report the types of PRO instruments used in MM, the frequency in which they are utilised in randomised controlled trials (RCTs), and the consistency of their reporting. Methods: The European Hematology Association (EHA) supports the development of guidelines for the use of PROs in adult patients with haematological malignancies. The first step is the present systematic review of the literature. MEDLINE and CENTRAL were searched for RCTs in MM between 2015 and 2020. Study design, characteristics of MM and its treatment, the primary outcomes, and the types of PRO instrument(s) were extracted using a predefined template. Additionally, in a stepwise approach, it was assessed whether the identified instruments had been validated for multiple myeloma patients, patients with haematological malignancies, or cancer patients. Results: Following screening for RCTs, 283 studies were included for review from 10,707 records retrieved, and 118 of these planned the use of PRO measures. Thirty-eight PRO instruments were reported. The most frequently used instrument (92 studies) was the EORTC QLQ-30. The EORTC-MY20 MM-specific questionnaire was the second most frequently used (50 studies), together with the EQ-5D (50 studies). Only 19 PRO instruments reported were consistent with the trial registry. Furthermore, in 58 publications, the information on PRO instruments differed between the publication and the trial registry. Further, information on PRO in HTA reports was available for 26 studies, of which 18 reports were consistent with the trial registries. Out of the 38 instruments used, six had been validated for patients with multiple myeloma (the most frequently used), six for patients with haematological malignancies, and 10 for cancer patients in general. Conclusions: The findings indicate that the measurement of PROs in RCTs for MM is underutilised, underreported, and often inconsistent. Guidelines for the appropriate use of PROs in MM are needed to ensure standardisation in selection and reporting. Furthermore, not all PRO instruments identified have been validated for myeloma patients or patients with haematological malignancies. Thus, guidelines for the appropriate use and reporting of PROs are needed in MM to ensure standardisation in the selection and reporting of PROs. Full article

(This article belongs to the Section Cancer Therapy)

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18 pages, 1786 KiB

Open AccessArticle

PKCβ Facilitates Leukemogenesis in Chronic Lymphocytic Leukaemia by Promoting Constitutive BCR-Mediated Signalling

by Jodie Hay, Anuradha Tarafdar, Ailsa K. Holroyd, Hothri A. Moka, Karen M. Dunn, Alzahra Alshayeb, Bryony H. Lloyd, Jennifer Cassels, Natasha Malik, Ashfia F. Khan, IengFong Sou, Jamie Lees, Hassan N. B. Almuhanna, Nagesh Kalakonda, Joseph R. Slupsky and Alison M. Michie

Cancers 2022, 14(23), 6006; https://doi.org/10.3390/cancers14236006 - 6 Dec 2022

Cited by 3 | Viewed by 2679

Abstract

B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic [...] Read more.

B cell antigen receptor (BCR) signalling competence is critical for the pathogenesis of chronic lymphocytic leukaemia (CLL). Defining key proteins that facilitate these networks aid in the identification of targets for therapeutic exploitation. We previously demonstrated that reduced PKCα function in mouse hematopoietic stem/progenitor cells (HPSCs) resulted in PKCβII upregulation and generation of a poor-prognostic CLL-like disease. Here, prkcb knockdown in HSPCs leads to reduced survival of PKCα-KR-expressing CLL-like cells, concurrent with reduced expression of the leukemic markers CD5 and CD23. SP1 promotes elevated expression of prkcb in PKCα-KR expressing cells enabling leukemogenesis. Global gene analysis revealed an upregulation of genes associated with B cell activation in PKCα-KR expressing cells, coincident with upregulation of PKCβII: supported by activation of key signalling hubs proximal to the BCR and elevated proliferation. Ibrutinib (BTK inhibitor) or enzastaurin (PKCβII inhibitor) treatment of PKCα-KR expressing cells and primary CLL cells showed similar patterns of Akt/mTOR pathway inhibition, supporting the role for PKCβII in maintaining proliferative signals in our CLL mouse model. Ibrutinib or enzastaurin treatment also reduced PKCα-KR-CLL cell migration towards CXCL12. Overall, we demonstrate that PKCβ expression facilitates leukemogenesis and identify that BCR-mediated signalling is a key driver of CLL development in the PKCα-KR model. Full article

(This article belongs to the Special Issue Advances in Chronic Lymphocytic Leukaemia (CLL) Research)

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4 pages, 210 KiB

Open AccessEditorial

The Emerging Role of NK Cells in Immune Checkpoint Blockade

by Alejandra Martinez-Perez, Candelaria Aguilar-Garcia and Segundo Gonzalez

Cancers 2022, 14(23), 6005; https://doi.org/10.3390/cancers14236005 - 6 Dec 2022

Cited by 2 | Viewed by 1403

Abstract

Natural killer (NK) cells are innate cytotoxic immune cells that play a fundamental role in anti-tumor immunity, particularly in hematological cancers, disseminated cancers, and metastasis [...] Full article

19 pages, 1906 KiB

Open AccessArticle

Pharmacological Inhibition of Lipid Import and Transport Proteins in Ovarian Cancer

by Lisa Lemberger, Renate Wagner, Gerwin Heller, Dietmar Pils and Thomas W. Grunt

Cancers 2022, 14(23), 6004; https://doi.org/10.3390/cancers14236004 - 5 Dec 2022

Cited by 7 | Viewed by 2324

Abstract

Ovarian cancer (OC) is the most lethal gynecological malignancy with a 5-year survival rate of 49%. This is caused by late diagnosis when cells have already metastasized into the peritoneal cavity and to the omentum. OC progression is dependent on the availability of [...] Read more.

Ovarian cancer (OC) is the most lethal gynecological malignancy with a 5-year survival rate of 49%. This is caused by late diagnosis when cells have already metastasized into the peritoneal cavity and to the omentum. OC progression is dependent on the availability of high-energy lipids/fatty acids (FA) provided by endogenous de novo biosynthesis and/or through import from the microenvironment. The blockade of these processes may thus represent powerful strategies against OC. While this has already been shown for inhibition of FA/lipid biosynthesis, evidence of the role of FA/lipid import/transport is still sparse. Therefore, we treated A2780 and SKOV3 OC cells with inhibitors of the lipid uptake proteins fatty acid translocase/cluster of differentiation 36 (FAT/CD36) and low-density lipoprotein (LDL) receptor (LDLR), as well as intracellular lipid transporters of the fatty acid-binding protein (FABP) family, fatty acid transport protein-2 (FATP2/SLC27A2), and ADP-ribosylation factor 6 (ARF6), which are overexpressed in OC. Proliferation was determined by formazan dye labeling/photometry and cell counting. Cell cycle analysis was performed by propidium iodide (PI) staining, and apoptosis was examined by annexin V/PI and active caspase 3 labeling and flow cytometry. RNA-seq data revealed altered stress and metabolism pathways. Overall, the small molecule inhibitors of lipid handling proteins BMS309403, HTS01037, NAV2729, SB-FI-26, and sulfosuccinimidyl oleate (SSO) caused a drug-specific, dose-/time-dependent inhibition of FA/LDL uptake, associated with reduced proliferation, cell cycle arrest, and apoptosis. Our findings indicate that OC cells are very sensitive to lipid deficiency. This dependency should be exploited for development of novel strategies against OC. Full article

(This article belongs to the Special Issue Metabolism in Ovarian Cancer)

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19 pages, 6101 KiB

Open AccessArticle

Resistin Promotes Nasopharyngeal Carcinoma Metastasis through TLR4-Mediated Activation of p38 MAPK/NF-κB Signaling Pathway

by Zongmeng Zhang, Jinlin Du, Qihua Xu, Yuyu Li, Sujin Zhou, Zhenggang Zhao, Yunping Mu, Allan Z. Zhao, Su-Mei Cao and Fanghong Li

Cancers 2022, 14(23), 6003; https://doi.org/10.3390/cancers14236003 - 5 Dec 2022

Cited by 7 | Viewed by 1690

Abstract

NPC is a type of malignant tumor with a high risk of local invasion and early distant metastasis. Resistin is an inflammatory cytokine that is predominantly produced from the immunocytes in humans. Accumulating evidence has suggested a clinical association of circulating resistin with [...] Read more.

NPC is a type of malignant tumor with a high risk of local invasion and early distant metastasis. Resistin is an inflammatory cytokine that is predominantly produced from the immunocytes in humans. Accumulating evidence has suggested a clinical association of circulating resistin with the risk of tumorigenesis and a relationship between blood resistin levels and the risk of cancer metastasis. In this study, we explored the blood levels and the role of resistin in NPC. High resistin levels in NPC patients were positively associated with lymph node metastasis, and resistin promoted the migration and invasion of NPC cells in vitro. These findings were also replicated in a mouse model of NPC tumor metastasis. We identified TLR4 as a functional receptor in mediating the pro-migratory effects of resistin in NPC cells. Furthermore, p38 MAPK and NF-κB were intracellular effectors that mediated resistin-induced EMT. Taken together, our results suggest that resistin promotes NPC metastasis by activating the TLR4/p38 MAPK/NF-κB signaling pathways. Full article

(This article belongs to the Special Issue Cell Plasticity in Cancer Progression: Role of EMT, Epigenetic Regulation and Host Microenvironment)

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12 pages, 279 KiB

Open AccessArticle

Dying with Cancer and COVID-19, with Special Reference to Lung Cancer: Frailty as a Risk Factor

by Peter Strang and Torbjörn Schultz

Cancers 2022, 14(23), 6002; https://doi.org/10.3390/cancers14236002 - 5 Dec 2022

Cited by 7 | Viewed by 1542

Abstract

Older age and frailty have been associated with COVID-19 deaths, but frailty has seldom been studied in the context of cancer. The aim of this paper was therefore to study frailty (measured using the Hospital Frailty Risk Score) and other risk factors in [...] Read more.

Older age and frailty have been associated with COVID-19 deaths, but frailty has seldom been studied in the context of cancer. The aim of this paper was therefore to study frailty (measured using the Hospital Frailty Risk Score) and other risk factors in patients who died with advanced cancer and a concomitant COVID-19 infection, with special reference to lung cancer. Of 4312 patients who died with cancer, 282 had concomitant COVID-19 (within the last 30 days), and these patients were significantly older, more often men, and residents of nursing homes. They often had less access to specialized palliative care, and they died more often in acute hospital settings. Patients with cancer who died with COVID-19 were more often frail (57% vs. 45%, p = 0.0002), and frailty was independently associated with COVID-19-related deaths, both in univariable and multivariable regression models, as well as when controlling for age, sex, socioeconomic factors on an area level, and comorbidity (measured using the Charlson Comorbidity Index). In the final multivariable model, where patients with cancer who died in nursing homes were excluded, belonging to the high-risk frailty group (OR 2.07 (1.31–3.27), p = 0.002) was the strongest prognostic variable in the model. In a separate analysis of a subgroup of deaths due to lung cancer (n = 653, of which 45 deaths occurred with concomitant COVID-19), the above associations were not significant, possibly due to too-few cases. In conclusion, frailty is a strong predictor of cancer deaths and should be addressed in cancer care. Full article

(This article belongs to the Special Issue Lung Cancer & COVID 19: Lessons, Experiences, Startegies)

4 pages, 956 KiB

Open AccessCorrection

Correction: Diamant et al. Effectiveness of Early Radical Cystectomy for High-Risk Non-Muscle Invasive Bladder Cancer. Cancers 2022, 14, 3797

by Elliott Diamant, Mathieu Roumiguié, Alexandre Ingels, Jérôme Parra, Dimitri Vordos, Anne-Sophie Bajeot, Emmanuel Chartier-Kastler, Michel Soulié, Alexandre de la Taille, Morgan Rouprêt and Thomas Seisen

Cancers 2022, 14(23), 6001; https://doi.org/10.3390/cancers14236001 - 5 Dec 2022

Cited by 1 | Viewed by 1274

Abstract

In the original article [...] Full article

(This article belongs to the Special Issue Advance and New Insights in Bladder Cancer)

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11 pages, 1594 KiB

Open AccessArticle

An Optimal Artificial Intelligence System for Real-Time Endoscopic Prediction of Invasion Depth in Early Gastric Cancer

by Jie-Hyun Kim, Sang-Il Oh, So-Young Han, Ji-Soo Keum, Kyung-Nam Kim, Jae-Young Chun, Young-Hoon Youn and Hyojin Park

Cancers 2022, 14(23), 6000; https://doi.org/10.3390/cancers14236000 - 5 Dec 2022

Cited by 6 | Viewed by 1771

Abstract

We previously constructed a VGG-16 based artificial intelligence (AI) model (image classifier [IC]) to predict the invasion depth in early gastric cancer (EGC) using endoscopic static images. However, images cannot capture the spatio-temporal information available during real-time endoscopy—the AI trained on static images [...] Read more.

We previously constructed a VGG-16 based artificial intelligence (AI) model (image classifier [IC]) to predict the invasion depth in early gastric cancer (EGC) using endoscopic static images. However, images cannot capture the spatio-temporal information available during real-time endoscopy—the AI trained on static images could not estimate invasion depth accurately and reliably. Thus, we constructed a video classifier [VC] using videos for real-time depth prediction in EGC. We built a VC by attaching sequential layers to the last convolutional layer of IC v2, using video clips. We computed the standard deviation (SD) of output probabilities for a video clip and the sensitivities in the manner of frame units to observe consistency. The sensitivity, specificity, and accuracy of IC v2 for static images were 82.5%, 82.9%, and 82.7%, respectively. However, for video clips, the sensitivity, specificity, and accuracy of IC v2 were 33.6%, 85.5%, and 56.6%, respectively. The VC performed better analysis of the videos, with a sensitivity of 82.3%, a specificity of 85.8%, and an accuracy of 83.7%. Furthermore, the mean SD was lower for the VC than IC v2 (0.096 vs. 0.289). The AI model developed utilizing videos can predict invasion depth in EGC more precisely and consistently than image-trained models, and is more appropriate for real-world situations. Full article

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19 pages, 2762 KiB

Open AccessArticle

Correlation of Transcriptomics and FDG-PET SUVmax Indicates Reciprocal Expression of Stemness-Related Transcription Factor and Neuropeptide Signaling Pathways in Glucose Metabolism of Ewing Sarcoma

by Carolin Prexler, Marie Sophie Knape, Janina Erlewein-Schweizer, Wolfgang Roll, Katja Specht, Klaus Woertler, Wilko Weichert, Irene von Luettichau, Claudia Rossig, Julia Hauer, Guenther H. S. Richter, Wolfgang Weber and Stefan Burdach

Cancers 2022, 14(23), 5999; https://doi.org/10.3390/cancers14235999 - 5 Dec 2022

Cited by 4 | Viewed by 2063

Abstract

Background: In Ewing sarcoma (EwS), long-term treatment effects and poor survival rates for relapsed or metastatic cases require individualization of therapy and the discovery of new treatment methods. Tumor glucose metabolic activity varies significantly between patients, and FDG-PET signals have been proposed as [...] Read more.

Background: In Ewing sarcoma (EwS), long-term treatment effects and poor survival rates for relapsed or metastatic cases require individualization of therapy and the discovery of new treatment methods. Tumor glucose metabolic activity varies significantly between patients, and FDG-PET signals have been proposed as prognostic factors. However, the biological basis for the generally elevated but variable glucose metabolism in EwS is not well understood. Methods: We retrospectively included 19 EwS samples (17 patients). Affymetrix gene expression was correlated with maximal standardized uptake value (SUVmax) using machine learning, linear regression modelling, and gene set enrichment analyses for functional annotation. Results: Expression of five genes correlated (MYBL2, ELOVL2, NETO2) or anticorrelated (FAXDC2, PLSCR4) significantly with SUVmax (adjusted p-value ≤ 0.05). Additionally, we identified 23 genes with large SUVmax effect size, which were significantly enriched for “neuropeptide Y receptor activity (GO:0004983)” (adjusted p-value = 0.0007). The expression of the members of this signaling pathway (NPY, NPY1R, NPY5R) anticorrelated with SUVmax. In contrast, three transcription factors associated with maintaining stemness displayed enrichment of their target genes with higher SUVmax: RNF2, E2F family, and TCF3. Conclusion: Our large-scale analysis examined comprehensively the correlations between transcriptomics and tumor glucose utilization. Based on our findings, we hypothesize that stemness may be associated with increased glucose uptake, whereas neuroectodermal differentiation may anticorrelate with glucose uptake. Full article

(This article belongs to the Special Issue Ewing Sarcoma: Basic Biology, Clinical Challenges and Future Perspectives)

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14 pages, 273 KiB

Open AccessArticle

Do Patient-Reported Upper-Body Symptoms Predict Breast Cancer-Related Lymphoedema: Results from a Population-Based, Longitudinal Breast Cancer Cohort Study

by Sandra C. Hayes, Matthew Dunn, Melanie L. Plinsinga, Hildegard Reul-Hirche, Yumeng Ren, E-Liisa Laakso and Melissa A. Troester

Cancers 2022, 14(23), 5998; https://doi.org/10.3390/cancers14235998 - 5 Dec 2022

Cited by 5 | Viewed by 2152

Abstract

The objectives of this work were to (i) describe upper-body symptoms post-breast cancer; (ii) explore the relationship between symptoms and upper-body function, breast cancer-related lymphoedema (BCRL), physical activity levels, and quality of life; and (iii) determine whether the presence of upper-body symptoms predicts [...] Read more.

The objectives of this work were to (i) describe upper-body symptoms post-breast cancer; (ii) explore the relationship between symptoms and upper-body function, breast cancer-related lymphoedema (BCRL), physical activity levels, and quality of life; and (iii) determine whether the presence of upper-body symptoms predicts BCRL. Nine symptoms, upper-body function, lymphoedema, physical activity, and quality of life were assessed in women with invasive breast cancer at baseline (2- to 9-months post-diagnosis; n = 2442), and at 2- and 7-years post-diagnosis. Mann–Whitney tests, unpaired t-tests, and chi-squared analyses were used to assess cross-sectional relationships, while regression analyses were used to assess the predictive relationships between symptoms at baseline, and BCRL at 2- and 7-years post-diagnosis. Symptoms are common post-breast cancer and persist at 2- and 7-years post-diagnosis. Approximately two in three women, and one in three women, reported >2 symptoms of at least mild severity, and of at least moderate severity, respectively. The presence of symptoms is associated with poorer upper-body function, and lower physical activity levels and quality of life. One or more symptoms of at least moderate severity increases the odds of developing BCRL by 2- and 7-years post-diagnosis (p < 0.05). Consequently, improved monitoring and management of symptoms following breast cancer have the potential to improve health outcomes. Full article

(This article belongs to the Special Issue New Insights in Lymphedema after Cancer to Enhance Clinical Practice)

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Graphical abstract

15 pages, 631 KiB

Open AccessReview

Selecting the Best Approach for the Treatment of Multiple Non-Metastatic Hepatocellular Carcinoma

by Gianluca Cassese, Ho-Seong Han, Jai Young Cho, Hae-Won Lee, Boram Lee and Roberto Ivan Troisi

Cancers 2022, 14(23), 5997; https://doi.org/10.3390/cancers14235997 - 5 Dec 2022

Cited by 8 | Viewed by 2391

Abstract

According to the Barcelona Clinic Liver Cancer (BCLC) staging system, the optimal strategy for patients with multiple HCC within the Milan Criteria is liver transplantation (LT). However, LT cannot be offered to all the patients due to organ shortages and long waiting lists, [...] Read more.

According to the Barcelona Clinic Liver Cancer (BCLC) staging system, the optimal strategy for patients with multiple HCC within the Milan Criteria is liver transplantation (LT). However, LT cannot be offered to all the patients due to organ shortages and long waiting lists, as well as because of the advanced disease carrying a high risk of poor outcomes. For early stages, liver resection (LR) or thermal ablation (TA) can be proposed, while trans-arterial chemoembolization (TACE) still remains the treatment of choice for intermediate stages (BCLC-B). Asian guidelines and the National Comprehensive Cancer Network suggest LR for resectable multinodular HCCs, even beyond Milan criteria. In this scenario, a growing body of evidence shows better outcomes after surgical resection when compared with TACE. Trans-arterial radioembolization (TARE) and stereotaxic body radiation therapy (SBRT) can also play an important role in this setting. Furthermore, the role of minimally invasive liver surgery (MILS) specifically for patients with multiple HCC is still not clear. This review aims to summarize current knowledge about the best therapeutical strategy for multiple HCC while focusing on the role of minimally invasive surgery and on the most attractive future perspectives. Full article

(This article belongs to the Special Issue Selecting the Best Approach for Single and Multiple Liver Tumors)

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14 pages, 3035 KiB

Open AccessSystematic Review

Deep Learning for the Diagnosis of Esophageal Cancer in Endoscopic Images: A Systematic Review and Meta-Analysis

by Md. Mohaimenul Islam, Tahmina Nasrin Poly, Bruno Andreas Walther, Chih-Yang Yeh, Shabbir Seyed-Abdul, Yu-Chuan (Jack) Li and Ming-Chin Lin

Cancers 2022, 14(23), 5996; https://doi.org/10.3390/cancers14235996 - 5 Dec 2022

Cited by 14 | Viewed by 2740

Abstract

Esophageal cancer, one of the most common cancers with a poor prognosis, is the sixth leading cause of cancer-related mortality worldwide. Early and accurate diagnosis of esophageal cancer, thus, plays a vital role in choosing the appropriate treatment plan for patients and increasing [...] Read more.

Esophageal cancer, one of the most common cancers with a poor prognosis, is the sixth leading cause of cancer-related mortality worldwide. Early and accurate diagnosis of esophageal cancer, thus, plays a vital role in choosing the appropriate treatment plan for patients and increasing their survival rate. However, an accurate diagnosis of esophageal cancer requires substantial expertise and experience. Nowadays, the deep learning (DL) model for the diagnosis of esophageal cancer has shown promising performance. Therefore, we conducted an updated meta-analysis to determine the diagnostic accuracy of the DL model for the diagnosis of esophageal cancer. A search of PubMed, EMBASE, Scopus, and Web of Science, between 1 January 2012 and 1 August 2022, was conducted to identify potential studies evaluating the diagnostic performance of the DL model for esophageal cancer using endoscopic images. The study was performed in accordance with PRISMA guidelines. Two reviewers independently assessed potential studies for inclusion and extracted data from retrieved studies. Methodological quality was assessed by using the QUADAS-2 guidelines. The pooled accuracy, sensitivity, specificity, positive and negative predictive value, and the area under the receiver operating curve (AUROC) were calculated using a random effect model. A total of 28 potential studies involving a total of 703,006 images were included. The pooled accuracy, sensitivity, specificity, and positive and negative predictive value of DL for the diagnosis of esophageal cancer were 92.90%, 93.80%, 91.73%, 93.62%, and 91.97%, respectively. The pooled AUROC of DL for the diagnosis of esophageal cancer was 0.96. Furthermore, there was no publication bias among the studies. The findings of our study show that the DL model has great potential to accurately and quickly diagnose esophageal cancer. However, most studies developed their model using endoscopic data from the Asian population. Therefore, we recommend further validation through studies of other populations as well. Full article

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11 pages, 1460 KiB

Open AccessArticle

Magnetic Resonance Spectroscopy Metabolites as Biomarkers of Disease Status in Pediatric Diffuse Intrinsic Pontine Gliomas (DIPG) Treated with Glioma-Associated Antigen Peptide Vaccines

by Ashok Panigrahy, Regina I. Jakacki, Ian F. Pollack, Rafael Ceschin, Hideho Okada, Marvin D. Nelson, Gary Kohanbash, Girish Dhall and Stefan Bluml

Cancers 2022, 14(23), 5995; https://doi.org/10.3390/cancers14235995 - 5 Dec 2022

Cited by 3 | Viewed by 2293

Abstract

Purpose: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. Methods: Single-voxel [...] Read more.

Purpose: Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive tumors with no currently available curative therapy. This study evaluated whether measurements of in vivo cell metabolites using magnetic resonance spectroscopy (MRS) may serve as biomarkers of response to therapy, including progression. Methods: Single-voxel MR spectra were serially acquired in two cohorts of patients with DIPG treated with radiation therapy (RT) with or without concurrent chemotherapy and prior to progression: 14 participants were enrolled in a clinical trial of adjuvant glioma-associated antigen peptide vaccines and 32 patients were enrolled who did not receive adjuvant vaccine therapy. Spearman correlations measured overall survival associations with absolute metabolite concentrations of myo-inositol (mI), creatine (Cr), and n-acetyl-aspartate (NAA) and their ratios relative to choline (Cho) during three specified time periods following completion of RT. Linear mixed-effects regression models evaluated the longitudinal associations between metabolite ratios and time from death (terminal decline). Results: Overall survival was not associated with metabolite ratios obtained shortly after RT (1.9–3.8 months post-diagnosis) in either cohort. In the vaccine cohort, an elevated mI/Cho ratio after 2–3 doses (3.9–5.2 months post-diagnosis) was associated with longer survival (rho = 0.92, 95% CI 0.67–0.98). Scans performed up to 6 months before death showed a terminal decline in the mI/Cho ratio, with an average of 0.37 ratio/month in vaccine patients (95% CI 0.11–0.63) and 0.26 (0.04–0.48) in the non-vaccine cohort. Conclusion: Higher mI/Cho ratios following RT, consistent with less proliferate tumors and decreased cell turnover, were associated with longer survival, suggesting that this ratio can serve as a biomarker of prognosis following RT. This finding was seen in both cohorts, although the association with OS was detected earlier in the vaccine cohort. Increased mI/Cho (possibly reflecting immune-effector cell influx into the tumor as a mechanism of tumor response) requires further study. Full article

(This article belongs to the Special Issue Brain Tumor Microenvironment)

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18 pages, 510 KiB

Open AccessArticle

Association of Pretreatment Physical and Geriatric Parameters with Treatment Tolerance and Survival in Elderly Patients with Stage I–II Non-Small Cell Lung Cancer: An Evaluation of Usual Care Data

by Melissa J. J. Voorn, Merle F. R. Bootsma, Gerben P. Bootsma, Vivian E. M. van Kampen-van den Boogaart, Geerten J. A. van Riet, Dirk K. de Ruysscher, Bart C. Bongers and Maryska L. G. Janssen-Heijnen

Cancers 2022, 14(23), 5994; https://doi.org/10.3390/cancers14235994 - 5 Dec 2022

Cited by 2 | Viewed by 1757

Abstract

In this study, the association of pretreatment physical and geriatric parameters with treatment tolerance and survival in elderly patients with stage I–II NSCLC was evaluated. Retrospective data for patients aged ≥70 years, diagnosed between 2016 and 2020 with stage I–II NSCLC, and who [...] Read more.

In this study, the association of pretreatment physical and geriatric parameters with treatment tolerance and survival in elderly patients with stage I–II NSCLC was evaluated. Retrospective data for patients aged ≥70 years, diagnosed between 2016 and 2020 with stage I–II NSCLC, and who underwent surgery or stereotactic ablative radiotherapy (SABR) in a large Dutch teaching hospital were retrieved from medical records. Associations of pretreatment physical and geriatric parameters with treatment tolerance and survival were analyzed. Of 160 patients, 49 of 104 (47%) patients who underwent surgery and 21 of 56 (38%) patients who received SABR did not tolerate treatment. In univariable analysis, World Health Organization (WHO) performance status ≥ 2, short nutritional assessment questionnaire score > 1, short physical performance battery score ≤ 9, and geriatric-8 score ≤ 14 were significantly associated with postoperative complications. Forced expiratory volume of one second < 80% of predicted was significantly associated with intolerance of SABR. In multivariable analysis, WHO performance status ≥ 2 and diffusing capacity for carbon monoxide < 80% were significantly associated with decreased overall survival. This is the first study that investigated the association between pretreatment physical and geriatric parameters and treatment outcomes in patients with stage I–II NSCLC. Evaluation of physical and geriatric parameters before treatment initiation seems highly recommended to select patients who might benefit from preventive interventions before and/or during treatment. Full article

(This article belongs to the Special Issue Lifestyle Modifications and Survival of Cancer Patients)

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18 pages, 3248 KiB

Open AccessArticle

Cytokines and Lymphoid Populations as Potential Biomarkers in Locally and Borderline Pancreatic Adenocarcinoma

by Iranzu González-Borja, Antonio Viúdez, Emilia Alors-Pérez, Saioa Goñi, Irene Amat, Ismael Ghanem, Roberto Pazo-Cid, Jaime Feliu, Laura Alonso, Carlos López, Virginia Arrazubi, Javier Gallego, Jairo Pérez-Sanz, Irene Hernández-García, Ruth Vera, Justo P Castaño and Joaquín Fernández-Irigoyen

Cancers 2022, 14(23), 5993; https://doi.org/10.3390/cancers14235993 - 5 Dec 2022

Cited by 3 | Viewed by 2192

Abstract

Despite its relative low incidence, PDAC is one of the most aggressive and lethal types of cancer, being currently the seventh leading cause of cancer death worldwide, with a 5-year survival rate of 10.8%. Taking into consideration the necessity to improve the prognosis [...] Read more.

Despite its relative low incidence, PDAC is one of the most aggressive and lethal types of cancer, being currently the seventh leading cause of cancer death worldwide, with a 5-year survival rate of 10.8%. Taking into consideration the necessity to improve the prognosis of these patients, this research has been focused on the discovery of new biomarkers. For this purpose, patients with BL and resectable disease were recruited. Serum cytokines and growth factors were monitored at different time points using protein arrays. Immune cell populations were determined by flow cytometry in peripheral blood as well as by immunohistochemistry (IHC) in tumor tissues. Several cytokines were found to be differentially expressed between the study subgroups. In the BL disease setting, two different scores were proven to be independent prognostic factors for progression-free survival (PFS) (based on IL-10, MDC, MIF, and eotaxin-3) and OS (based on eotaxin-3, NT-3, FGF-9, and IP10). In the same context, CA19-9 was found to play a role as independent prognostic factor for OS. Eotaxin-3 and MDC cytokines for PFS, and eotaxin-3, NT-3, and CKβ8-1 for OS, were shown to be predictive biomarkers for nab-paclitaxel and gemcitabine regimen. Similarly, oncostatin, BDNF, and IP10 cytokines were proven to act as predictive biomarkers regarding PFS, for FOLFIRINOX regimen. In the resectable cohort, RANTES, TIMP-1, FGF-4, and IL-10 individually differentiated patients according to their cancer-associated survival. Regarding immune cell populations, baseline high levels of circulating B lymphocytes were related to a significantly longer OS, while these levels significantly decreased as progression occurred. Similarly, baseline high levels of helper lymphocytes (CD4+), low levels of cytotoxic lymphocytes (CD8+), and a high CD4/CD8 ratio, were related to a significantly longer PFS. Finally, high levels of CD4+ and CD8+ intratumoural infiltration was associated with significantly longer PFS. In conclusion, in this study we were able to identify several prognostic and predictive biomarker candidates in patients diagnosed of resectable or BL PDAC. Full article

(This article belongs to the Special Issue Early Detection and Diagnosis of Pancreatic Cancer)

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18 pages, 1964 KiB

Open AccessArticle

Inhibition of Vascular Endothelial Growth Factor Protects against the Development of Oxaliplatin-Induced Sinusoidal Obstruction Syndrome in Wild-Type but Not in CD39-Null Mice

by Sebastian Knitter, Gregor Duwe, Anika Sophie Beierle, Sina Pesthy, Paul Viktor Ritschl, Karl Herbert Hillebrandt, Alexander Arnold, Thomas Malinka, Dominik Paul Modest, Marcus Bahra, Johann Pratschke, Igor Maximilian Sauer, Moritz Schmelzle and Andreas Andreou

Cancers 2022, 14(23), 5992; https://doi.org/10.3390/cancers14235992 - 5 Dec 2022

Viewed by 1779

Abstract

(1) Background: Sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy is associated with unfavorable outcomes after partial hepatectomy for colorectal liver metastases (CLM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), may prevent SOS development. We investigated the impact of VEGF-inhibition [...] Read more.

(1) Background: Sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy is associated with unfavorable outcomes after partial hepatectomy for colorectal liver metastases (CLM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), may prevent SOS development. We investigated the impact of VEGF-inhibition on the development of SOS in a murine model. (2) Methods: Male wild-type and CD39-null mice received oxaliplatin, additional anti-VEGF (OxAV), or controls, and were sacrificed or subjected to major partial hepatectomy (MH). Specimen were used for histological analysis of SOS. Liver damage was assessed by plasma transaminases. The VEGF pathway was elucidated by quantitative PCR of liver tissue and protein analysis of plasma. (3) Results: Mice treated with oxaliplatin developed SOS. Concomitant anti-VEGF facilitated a reduced incidence of SOS, but not in CD39-null mice. SOS was associated with increased plasma VEGF-A and decreased hepatocyte growth factor (HGF). After OxAV treatment, VEGF-R2 was upregulated in wild-type but downregulated in CD39-null mice. Oxaliplatin alone was associated with higher liver damage after MH than in mice with concomitant VEGF-inhibition. (4) Conclusions: We established a murine model of oxaliplatin-induced SOS and provided novel evidence on the protective effect of VEGF-inhibition against the development of SOS that may be associated with changes in the pathway of VEGF and its receptor VEGF-R2. Full article

(This article belongs to the Special Issue Clinical and Translational Research in Gastrointestinal Cancers)

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11 pages, 829 KiB

Open AccessArticle

TRICIN: A Phase II Trial on the Efficacy of Topical TRIchloroacetic Acid in Patients with Cervical Intraepithelial Neoplasia

by Richard Schwameis, Julia Ganhoer-Schimboeck, Victoria Laudia Hadjari, Lukas Hefler, Birgit Bergmeister, Tatjana Küssel, Gunda Gittler, Theodora Steindl-Schoenhuber and Christoph Grimm

Cancers 2022, 14(23), 5991; https://doi.org/10.3390/cancers14235991 - 5 Dec 2022

Cited by 1 | Viewed by 2237

Abstract

Data on non-surgical treatment approaching persistent cervical intraepithelial neoplasia (CIN) are scarce. Retrospective analysis suggest high efficacy of topical treatment with trichloroacetic acid (TCA). This prospective phase II study set out to investigate the efficacy of a single application of 85% TCA in [...] Read more.

Data on non-surgical treatment approaching persistent cervical intraepithelial neoplasia (CIN) are scarce. Retrospective analysis suggest high efficacy of topical treatment with trichloroacetic acid (TCA). This prospective phase II study set out to investigate the efficacy of a single application of 85% TCA in the treatment of CIN I/II. Patients with CIN I/II were treated a single time with 85% TCA. After three and six months colposcopic, histologic, and HPV evaluation was performed. The primary endpoint was treatment efficacy defined as complete histologic remission six months after treatment. The secondary endpoint was HPV clearance six months after treatment. A total of 102 patients with CIN I/II were included into this trial. Complete histologic remission rates were 75.5% and 78.4% three and six months after TCA treatment, respectively. Clearance rates of HPV 16, 18 and other high risk types were 76.5%, 91.7%, 68.7% after six months, respectively. Side effects of TCA were mild and lasted usually less than 30 min. This is the first prospective trial reporting high histologic complete remission rates in patients with CIN I/II after a single 85% TCA treatment. In the future, TCA may represent an effective and feasible non-surgical treatment approach for CIN. Full article

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

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6 pages, 227 KiB

Open AccessCommunication

The Use of Mechanical Bowel Preparation and Oral Antibiotic Prophylaxis in Elective Colorectal Surgery: A Call for Change in Practice

by Nikoletta A. Petrou and Christos Kontovounisios

Cancers 2022, 14(23), 5990; https://doi.org/10.3390/cancers14235990 - 4 Dec 2022

Cited by 4 | Viewed by 2897

Abstract

Elective colorectal surgery is associated with one of the highest rates of surgical site infections (SSIs), which result in prolonged length of stay, morbidity, and mortality for these patients and have a significant financial burden to healthcare systems. In an effort to reduce [...] Read more.

Elective colorectal surgery is associated with one of the highest rates of surgical site infections (SSIs), which result in prolonged length of stay, morbidity, and mortality for these patients and have a significant financial burden to healthcare systems. In an effort to reduce the frequency of SSI rates associated with colorectal surgery, the 2018 World Health Organisation (WHO) guidelines recommend the routine use of mechanical bowel preparation (MBP) and oral antibiotic prophylaxis (OAP) in adult patients undergoing elective colorectal surgery. However, this recommendation remains a topic of debate internationally. The National Institute of Clinical Excellence (NICE) guidelines, last revised in 2019, recommend against the routine use of MBP and do not address the issue of OAP. In this communication, we reviewed the current guidelines and examined the most recent evidence from randomised-control trials (RCTs) and meta-analyses on the effect of MBP and OAP on SSI rates since the 2019 NICE guideline review. This recent evidence clearly demonstrated an SSI-risk-reduction benefit with the additional use of OAP and the combination of MBP and OAP in this group of patients, and we therefore highlight the need for change of the current NICE guidelines. Full article

(This article belongs to the Special Issue Surgical Treatment of Gastrointestinal Cancers)

17 pages, 1272 KiB

Open AccessReview

Viewing AML through a New Lens: Technological Advances in the Study of Epigenetic Regulation

by Laura C. Godfrey and Alba Rodriguez-Meira

Cancers 2022, 14(23), 5989; https://doi.org/10.3390/cancers14235989 - 4 Dec 2022

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Abstract

Epigenetic modifications, such as histone modifications and DNA methylation, are essential for ensuring the dynamic control of gene regulation in every cell type. These modifications are associated with gene activation or repression, depending on the genomic context and specific type of modification. In [...] Read more.

Epigenetic modifications, such as histone modifications and DNA methylation, are essential for ensuring the dynamic control of gene regulation in every cell type. These modifications are associated with gene activation or repression, depending on the genomic context and specific type of modification. In both cases, they are deposited and removed by epigenetic modifier proteins. In acute myeloid leukemia (AML), the function of these proteins is perturbed through genetic mutations (i.e., in the DNA methylation machinery) or translocations (i.e., MLL-rearrangements) arising during leukemogenesis. This can lead to an imbalance in the epigenomic landscape, which drives aberrant gene expression patterns. New technological advances, such as CRISPR editing, are now being used to precisely model genetic mutations and chromosomal translocations. In addition, high-precision epigenomic editing using dCas9 or CRISPR base editing are being used to investigate the function of epigenetic mechanisms in gene regulation. To interrogate these mechanisms at higher resolution, advances in single-cell techniques have begun to highlight the heterogeneity of epigenomic landscapes and how these impact on gene expression within different AML populations in individual cells. Combined, these technologies provide a new lens through which to study the role of epigenetic modifications in normal hematopoiesis and how the underlying mechanisms can be hijacked in the context of malignancies such as AML. Full article

(This article belongs to the Special Issue Multi-Faceted Epigenetic Dysregulation in Acute Myeloid Leukemia)

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Open AccessArticle

Risk Assessment of Postoperative Pneumonia in Cancer Patients Using a Common Data Model

by Yong Hoon Lee, Do-Hoon Kim, Jisun Kim and Jaetae Lee

Cancers 2022, 14(23), 5988; https://doi.org/10.3390/cancers14235988 - 4 Dec 2022

Cited by 3 | Viewed by 2004

Abstract

The incidence of postoperative pneumonia (POP) in patients with cancer is high, but its incidence following major cancer surgeries is unclear. Therefore, we investigated the incidence and risk factors of POP after surgery in patients with the five most common cancers in Korea [...] Read more.

The incidence of postoperative pneumonia (POP) in patients with cancer is high, but its incidence following major cancer surgeries is unclear. Therefore, we investigated the incidence and risk factors of POP after surgery in patients with the five most common cancers in Korea using a common data model (CDM). Patients aged >19 years who underwent gastric, colon, liver, lung, or breast cancer surgery between January 2011 and December 2020 were included, excluding patients who underwent chemotherapy or radiotherapy. Pneumonia was defined as a pneumonia diagnosis code in patients hospitalized postoperatively. Gastric, colon, lung, breast, and liver cancers were noted in 4004 (47.4%), 622 (7.4%), 2022 (24%), 958 (11.3%), and 839 (9.9%) of 8445 patients, respectively. The cumulative POP incidence was 3.1% (n = 262), with the highest incidence in lung cancer (n = 91, 4.5%), followed by gastric (n = 133, 3.3%), colon (n = 19, 3.1%), liver (n = 14, 1.7%), and breast (n = 5, 0.5%) cancers. In multivariable analysis, older age, male sex, history of chronic pulmonary disease, mood disorder, and cerebrovascular disease were POP predictors. The cumulative POP incidence in the five cancers using the CDM was approximately 3%. Older age, male sex, chronic pulmonary disease, mood disorder, and cerebrovascular disease were POP risk factors in patients with cancer. Full article

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Cancers, Volume 14, Issue 23 (December-1 2022) – 296 articles

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