Cancers

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14 pages, 1902 KiB

Open AccessArticle

Exploring Volatile Organic Compounds in Breath for High-Accuracy Prediction of Lung Cancer

by Ping-Hsien Tsou, Zong-Lin Lin, Yu-Chiang Pan, Hui-Chen Yang, Chien-Jen Chang, Sheng-Kai Liang, Yueh-Feng Wen, Chia-Hao Chang, Lih-Yu Chang, Kai-Lun Yu, Chia-Jung Liu, Li-Ta Keng, Meng-Rui Lee, Jen-Chung Ko, Guan-Hua Huang and Yaw-Kuen Li

Cancers 2021, 13(6), 1431; https://doi.org/10.3390/cancers13061431 - 21 Mar 2021

Cited by 54 | Viewed by 7136

Abstract

(1) Background: Lung cancer is silent in its early stages and fatal in its advanced stages. The current examinations for lung cancer are usually based on imaging. Conventional chest X-rays lack accuracy, and chest computed tomography (CT) is associated with radiation exposure and [...] Read more.

(1) Background: Lung cancer is silent in its early stages and fatal in its advanced stages. The current examinations for lung cancer are usually based on imaging. Conventional chest X-rays lack accuracy, and chest computed tomography (CT) is associated with radiation exposure and cost, limiting screening effectiveness. Breathomics, a noninvasive strategy, has recently been studied extensively. Volatile organic compounds (VOCs) derived from human breath can reflect metabolic changes caused by diseases and possibly serve as biomarkers of lung cancer. (2) Methods: The selected ion flow tube mass spectrometry (SIFT-MS) technique was used to quantitatively analyze 116 VOCs in breath samples from 148 patients with histologically confirmed lung cancers and 168 healthy volunteers. We used eXtreme Gradient Boosting (XGBoost), a machine learning method, to build a model for predicting lung cancer occurrence based on quantitative VOC measurements. (3) Results: The proposed prediction model achieved better performance than other previous approaches, with an accuracy, sensitivity, specificity, and area under the curve (AUC) of 0.89, 0.82, 0.94, and 0.95, respectively. When we further adjusted the confounding effect of environmental VOCs on the relationship between participants’ exhaled VOCs and lung cancer occurrence, our model was improved to reach 0.92 accuracy, 0.96 sensitivity, 0.88 specificity, and 0.98 AUC. (4) Conclusion: A quantitative VOCs databank integrated with the application of an XGBoost classifier provides a persuasive platform for lung cancer prediction. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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13 pages, 1890 KiB

Open AccessCommunication

Worm-Based Microfluidic Biosensor for Real-Time Assessment of the Metastatic Status

by Jing Zhang, Song Lin Chua and Bee Luan Khoo

Cancers 2021, 13(4), 873; https://doi.org/10.3390/cancers13040873 - 19 Feb 2021

Cited by 17 | Viewed by 3894

Abstract

Background: Metastasis is a complex process that affects patient treatment and survival. To routinely monitor cancer plasticity and guide treatment strategies, it is highly desired to provide information about metastatic status in real-time. Here, we proposed a worm-based (WB) microfluidic biosensor to rapidly [...] Read more.

Background: Metastasis is a complex process that affects patient treatment and survival. To routinely monitor cancer plasticity and guide treatment strategies, it is highly desired to provide information about metastatic status in real-time. Here, we proposed a worm-based (WB) microfluidic biosensor to rapidly monitor biochemical cues related to metastasis in a well-defined environment. Compared to conventional biomarker-based methods, the WB biosensor allowed high throughput screening under low cost, requiring only visual quantification of outputs; Methods: Caenorhabditis elegans were placed in the WB biosensor and exposed to samples conditioned with cancer cell clusters. The chemotactic preference of these worms was observed under discontinuous imaging to minimize the impact on physiological activity; Results: A chemotaxis index (CI) was defined to standardize the quantitative assessment from the WB biosensor, where moderate (3.24–6.5) and high (>6.5) CI levels reflected increased metastasis risk and presence of metastasis, respectively. We demonstrated that the secreted metabolite glutamate was a chemorepellent, and larger clusters associated with increased metastatic potential also enhanced CI levels; Conclusions: Overall, this study provided a proof of concept for the WB biosensors in assessing metastasis status, with the potential to evaluate patient-derived cancer clusters for routine management. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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15 pages, 1397 KiB

Open AccessArticle

Fecal Immunochemical Tests Detect Screening Participants with Multiple Advanced Adenomas Better than T1 Colorectal Cancers

by Anton Gies, Tobias Niedermaier, Laura Fiona Gruner, Thomas Heisser, Petra Schrotz-King and Hermann Brenner

Cancers 2021, 13(4), 644; https://doi.org/10.3390/cancers13040644 - 5 Feb 2021

Cited by 4 | Viewed by 2231

Abstract

Background: Fecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screening. The detection of early-stage cancer and advanced adenoma (AA), the most important premalignant lesion, is highly relevant to reducing CRC-related deaths. We aimed to assess sensitivity for the detection of [...] Read more.

Background: Fecal immunochemical tests (FITs) are widely used for colorectal cancer (CRC) screening. The detection of early-stage cancer and advanced adenoma (AA), the most important premalignant lesion, is highly relevant to reducing CRC-related deaths. We aimed to assess sensitivity for the detection of CRC and AA stratified by tumor stage; number; size; histology of AA; and by location, age, sex, and body mass index (BMI). Methods: Participants of screening colonoscopy (n = 2043) and newly diagnosed CRC patients (n = 184) provided a stool sample before bowel preparation or CRC surgery. Fecal hemoglobin concentration was determined in parallel by nine different quantitative FITs among 94 CRC patients, 200 AA cases, and 300 participants free of advanced neoplasm. Sensitivities were calculated at original cutoffs and at adjusted cutoffs, yielding 93% specificity among all FITs. Results: At adjusted cutoffs, UICC stage I cancers yielded consistently lower sensitivities (range: 62–68%) compared to stage II–IV cancers (range: 73–89%). An even stronger gradient was observed according to T status, with substantially lower sensitivities for T1 (range: 39–57%) than for T2–T4 cancers (range: 71–100%). Sensitivities for the detection of participants with multiple AAs ranged from 55% to 64% and were by up to 25% points higher than sensitivities for T1 cancers. Conclusions: FITs detect stage I cancers and especially T1 cancers at substantially lower sensitivities than more advanced cancer stages. Participants with multiple AAs were detected with slightly lower sensitivities than stage I cancers and with even higher sensitivities than T1 cancers. Further research should focus on improving the detection of early-stage cancers. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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14 pages, 2764 KiB

Open AccessFeature PaperArticle

Circulating microRNA Panel as a Potential Novel Biomarker for Oral Squamous Cell Carcinoma Diagnosis

by Kodai Nakamura, Naomi Hiyake, Tomofumi Hamada, Seiya Yokoyama, Kazuki Mori, Kouta Yamashiro, Mahiro Beppu, Yasuaki Sagara, Yoshiaki Sagara and Tsuyoshi Sugiura

Cancers 2021, 13(3), 449; https://doi.org/10.3390/cancers13030449 - 25 Jan 2021

Cited by 26 | Viewed by 3683

Abstract

A lack of reliable biomarkers for oral squamous cell carcinoma (OSCC) poses a major clinical issue. The sensitivity and specificity of classical serum tumor markers, such as the squamous cell carcinoma antigen (SCC-Ag), are quite poor, especially for early detection. This study aimed [...] Read more.

A lack of reliable biomarkers for oral squamous cell carcinoma (OSCC) poses a major clinical issue. The sensitivity and specificity of classical serum tumor markers, such as the squamous cell carcinoma antigen (SCC-Ag), are quite poor, especially for early detection. This study aimed to identify specific serum miRNAs potentially serving as OSCC biomarkers. The expression levels of candidate miRNAs in serum samples from 40 OSCC patients and 40 healthy controls were quantitatively analyzed via microarray and reverse transcription PCR (RT-PCR) analyses. To enhance the accuracy of detection, we used Fisher’s linear discriminant analysis to establish a diagnostic model that incorporated a combination of selected miRNAs. Consequently, miR-19a and miR-20a were significantly upregulated in the patient group (p = 0.014 and 0.036, respectively), whereas miR-5100 was downregulated (p = 0.001). We found that a combination of six miRNAs (miR-24, miR-20a, miR-122, miR-150, miR-4419a, and miR-5100) could distinguish between OSCC and the control group with a higher degree of accuracy (Area Under the Curve, AUC: 0.844, sensitivity: 55%, and specificity: 92.5%). Furthermore, compared to serum SCC antigen, the 6-miRNA panel could accurately detect the presence of OSCC. The present specific miRNAs panel may serve as a novel candidate biomarker of oral cancer. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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18 pages, 3588 KiB

Open AccessArticle

Development of Sensitive Droplet Digital PCR Assays for Detecting Urinary TERT Promoter Mutations as Non-Invasive Biomarkers for Detection of Urothelial Cancer

by Md Ismail Hosen, Nathalie Forey, Geoffroy Durand, Catherine Voegele, Selin Bilici, Patrice Hodonou Avogbe, Tiffany Myriam Delhomme, Matthieu Foll, Arnaud Manel, Emmanuel Vian, Sonia Meziani, Berengere De Tilly, Gilles Polo, Olesia Lole, Pauline Francois, Antoine Boureille, Eduard Pisarev, Andrei R. O. S. E. Salas, Sara Monteiro-Reis, Rui Henrique, Graham Byrnes, Carmen Jeronimo, Ghislaine Scelo, James D. McKay, Florence Le Calvez-Kelm and Maria Zvereva Show full author list Hide full author list

Cancers 2020, 12(12), 3541; https://doi.org/10.3390/cancers12123541 - 27 Nov 2020

Cited by 29 | Viewed by 5336

Abstract

Somatic mutations in the telomerase reverse transcriptase (TERT) promoter regions are frequent events in urothelial cancer (UC) and their detection in urine (supernatant cell-free DNA or DNA from exfoliated cells) could serve as putative non-invasive biomarkers for UC detection and monitoring. [...] Read more.

Somatic mutations in the telomerase reverse transcriptase (TERT) promoter regions are frequent events in urothelial cancer (UC) and their detection in urine (supernatant cell-free DNA or DNA from exfoliated cells) could serve as putative non-invasive biomarkers for UC detection and monitoring. However, detecting these tumor-borne mutations in urine requires highly sensitive methods, capable of measuring low-level mutations. In this study, we developed sensitive droplet digital PCR (ddPCR) assays for detecting TERT promoter mutations (C228T, C228A, CC242-243TT, and C250T). We tested the C228T and C250T ddPCR assays on all samples with sufficient quantity of urinary DNA (urine supernatant cell-free DNA (US cfDNA) or urine pellet cellular DNA (UP cellDNA)) from the DIAGURO (n = 89/93 cases and n = 92/94 controls) and from the IPO-PORTO (n = 49/50 cases and n = 50/50 controls) series that were previously screened with the UroMuTERT assay and compared the performance of the two approaches. In the DIAGURO series, the sensitivity and specificity of the ddPCR assays for detecting UC using either US cfDNA or UP cellDNA were 86.8% and 92.4%. The sensitivity was slightly higher than that of the UroMuTERT assay in the IPO-PORTO series (67.4% vs. 65.3%, respectively), but not in the DIAGURO series (86.8% vs. 90.7%). The specificity was 100% in the IPO-PORTO controls for both the UroMuTERT and ddPCR assays, whereas in the DIAGURO series, the specificity dropped for ddPCR (92.4% versus 95.6%). Overall, an almost perfect agreement between the two methods was observed for both US cfDNA (n = 164; kappa coefficient of 0.91) and UP cellDNA (n = 280; kappa coefficient of 0.94). In a large independent series of serial urine samples from DIAGURO follow-up BC cases (n = 394), the agreement between ddPCR and UroMuTERT was (i) strong (kappa coefficient of 0.87), regardless of urine DNA types (kappa coefficient 0.89 for US cfDNA and 0.85 for UP cellDNA), (ii) the highest for samples with mutant allelic fractions (MAFs) > 2% (kappa coefficient of 0.99) and (iii) only minimal for the samples with the lowest MAFs (< 0.5%; kappa coefficient 0.32). Altogether, our results indicate that the two methods (ddPCR and UroMuTERT) for detecting urinary TERT promoter mutations are comparable and that the discrepancies relate to the detection of low-allelic fraction mutations. The simplicity of the ddPCR assays makes them suitable for implementation in clinical settings. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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16 pages, 2911 KiB

Open AccessArticle

Comprehensive Gene Mutation Profiling of Circulating Tumor DNA in Ovarian Cancer: Its Pathological and Prognostic Impact

by Tomoko Noguchi, Naoyuki Iwahashi, Kazuko Sakai, Kaho Matsuda, Hitomi Matsukawa, Saori Toujima, Kazuto Nishio and Kazuhiko Ino

Cancers 2020, 12(11), 3382; https://doi.org/10.3390/cancers12113382 - 16 Nov 2020

Cited by 17 | Viewed by 4621

Abstract

Liquid biopsies from circulating tumor DNA (ctDNA) have been employed recently as a non-invasive diagnostic tool for detecting cancer-specific gene mutations. Here, we show the comprehensive gene mutation profiles of ctDNA in 51 patients with different histological subtypes of stage I–IV ovarian cancer, [...] Read more.

Liquid biopsies from circulating tumor DNA (ctDNA) have been employed recently as a non-invasive diagnostic tool for detecting cancer-specific gene mutations. Here, we show the comprehensive gene mutation profiles of ctDNA in 51 patients with different histological subtypes of stage I–IV ovarian cancer, and their association with clinical outcomes. The ctDNA extracted from pre-treatment patients’ plasma were analyzed using Cancer Personalized Profiling by Deep Sequencing targeting 197 genes. Of 51 patients, 48 (94%) showed one or more non-synonymous somatic mutations, including TP53 (37.3%), APC (17.6%), KRAS (15.7%), EGFR (13.7%), MET (11.8%), PIK3CA (11.8%), NPAP1 (11.8%), and ALK (9.8%). The most frequently mutated genes were as follows: TP53 in high-grade serous carcinoma (66.7%), APC in clear cell carcinoma (30.8%), PIK3CA in endometrioid carcinoma (40%), and KRAS in mucinous carcinoma (66.7%). Higher cell-free (cf)DNA concentration significantly correlated with worse progression-free survival (PFS) in all patients as well as stage III–IV patients (p = 0.01 and 0.005, respectively). Further, patients with any pathogenic mutations showed significantly worse PFS (p = 0.048). Blood tumor mutational burden detected from ctDNA did not significantly correlate with the histological subtypes or survival. Collectively, clinico-genomic profiles of individual ovarian cancer patients could be identified using ctDNA and may serve as a useful prognostic indicator. These findings suggest that ctDNA-based gene profiling might help in establishing personalized therapeutic strategies. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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12 pages, 1615 KiB

Open AccessArticle

The Trained Sniffer Dog Could Accurately Detect the Urine Samples from the Patients with Cervical Cancer, and Even Cervical Intraepithelial Neoplasia Grade 3: A Pilot Study

by Akihito Yamamoto, Seiryu Kamoi, Keisuke Kurose, Marie Ito, Toshiyuki Takeshita, Shoko Kure, Katsuichi Sakamoto, Yuji Sato and Masao Miyashita

Cancers 2020, 12(11), 3291; https://doi.org/10.3390/cancers12113291 - 6 Nov 2020

Cited by 10 | Viewed by 3686

Abstract

(1) Background: Previous reports have indicated that cancers of the stomach, lung, and pancreas can be detected by dog sniffing, but results have been varied. Here, a highly trained dog was used to determine whether urine from patients with cervical premalignant lesions and [...] Read more.

(1) Background: Previous reports have indicated that cancers of the stomach, lung, and pancreas can be detected by dog sniffing, but results have been varied. Here, a highly trained dog was used to determine whether urine from patients with cervical premalignant lesions and malignant tumors have a cancer-specific scent. (2) Methods: A total of 195 urine samples were collected from patients with cervical cancer, cervical intraepithelial neoplasia grade 3 (CIN3), benign uterine diseases, and healthy volunteers. Each test was performed using one urine sample from a cancer patient and four samples from different controls. Each of the five urine samples was placed in a separate box. When the cancer sniffing dog stopped and sat in front of the box with a sample from a cancer patient, the test was considered as positive. (3) Results: 83 patients with cervical cancer (34 cases of cervical cancer and 49 cases of cervical intraepithelial neoplasia grade 3), 49 patients with uterine benign diseases, and 63 healthy volunteers were enrolled, and their urine samples were collected. In 83 times out of 83 runs in a double-blind test, the trained dog could correctly identify urine samples of cervical cancer patients. (4) Conclusion: A trained dog could accurately distinguish the urine of all patients with cervical cancer or CIN3, regardless of the degree of cancer progression. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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16 pages, 4834 KiB

Open AccessArticle

Non-Invasive Early Detection of Oral Cancers Using Fluorescence Visualization with Optical Instruments

by Takamichi Morikawa, Takahiko Shibahara, Takeshi Nomura, Akira Katakura and Masayuki Takano

Cancers 2020, 12(10), 2771; https://doi.org/10.3390/cancers12102771 - 27 Sep 2020

Cited by 20 | Viewed by 8103

Abstract

Background: Oral cancer screening is important for early detection and early treatment, which help improve survival rates. Biopsy is the gold standard for a definitive diagnosis but is invasive and painful, while fluorescence visualization is non-invasive, convenient, and real-time, and examinations can be [...] Read more.

Background: Oral cancer screening is important for early detection and early treatment, which help improve survival rates. Biopsy is the gold standard for a definitive diagnosis but is invasive and painful, while fluorescence visualization is non-invasive, convenient, and real-time, and examinations can be repeated using optical instruments. The purpose of this study was to clarify the usefulness of fluorescence visualization in oral cancer screening. Methods: A total of 502 patients, who were examined using fluorescence visualization with optical instruments in our hospitals between 2014 and 2019, were enrolled in this study. The final diagnosis was performed by pathological examination. Fluorescence visualization was analyzed using subjective and objective evaluations. Results: Subjective evaluations for detecting oral cancer offered 96.8% sensitivity and 48.4% specificity. Regarding the objective evaluations, sensitivity and specificity were 43.7% and 84.6% for mean green value, 55.2% and 67.0% for median green value, 82.0% and 44.2% for coefficient of variation of value, 59.6% and 45.3% for skewness, and 85.1% and 75.8% for value ratio. For the sub-analysis of oral cancer, all factors on objective and subjective evaluation showed no significant difference. Conclusions: Fluorescence visualization with subjective and objective evaluation is useful for oral cancer screening. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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16 pages, 1811 KiB

Open AccessArticle

Isolation and Enumeration of CTC in Colorectal Cancer Patients: Introduction of a Novel Cell Imaging Approach and Comparison to Cellular and Molecular Detection Techniques

by Alexander Hendricks, Burkhard Brandt, Reinhild Geisen, Katharina Dall, Christian Röder, Clemens Schafmayer, Thomas Becker, Sebastian Hinz and Susanne Sebens

Cancers 2020, 12(9), 2643; https://doi.org/10.3390/cancers12092643 - 16 Sep 2020

Cited by 18 | Viewed by 3941

Abstract

Circulating tumour cells (CTC) were proven to be prognostically relevant in cancer treatment, e.g., in colorectal cancer (CRC). This study validates a molecular detection technique through using a novel cell imaging approach for CTC detection and enumeration, in comparison to a size-based cellular [...] Read more.

Circulating tumour cells (CTC) were proven to be prognostically relevant in cancer treatment, e.g., in colorectal cancer (CRC). This study validates a molecular detection technique through using a novel cell imaging approach for CTC detection and enumeration, in comparison to a size-based cellular and correlated the data to clinico-pathological characteristics. Overall, 57 CRC patients were recruited for this prospective study. Blood samples were analysed for CTCs by three methods: (1) Epithelial marker immunofluorescence staining combined with automated microscopy using the NYONE^® cell imager; (2) isolation by size using membrane filtration with the ScreenCell^® Cyto IS device and immunofluorescence staining; (3) detection by semi-quantitative Cytokeratin-20 RT-qPCR. Enumeration data were compared and correlated with clinic-pathological parameters. CTC were detected by either approach; however, with varying positivity rates: NYONE^® 36.4%, ScreenCell^® 100%, and PCR 80.5%. All methods revealed a positive correlation of CTC presence and higher tumour burden, which was most striking using the ScreenCell^® device. Generally, no intercorrelation of CTC presence emerged amongst the applied techniques. Overall, enumeration of CTC after isolation by size demonstrated to be the most reliable strategy for the detection of CTC in CRC patients. Ongoing studies will have to unravel the prognostic value of this finding, and validate this approach in a larger cohort. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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16 pages, 889 KiB

Open AccessArticle

Prospective Study Using Plasma Apolipoprotein A2-Isoforms to Screen for High-Risk Status of Pancreatic Cancer

by Yu Sato, Takashi Kobayashi, Shin Nishiumi, Akihiko Okada, Tsuyoshi Fujita, Tsuyoshi Sanuki, Masao Kobayashi, Masakyo Asahara, Masayasu Adachi, Arata Sakai, Hideyuki Shiomi, Atsuhiro Masuda, Masaru Yoshida, Keiko Takeuchi, Yuzo Kodama, Hiromu Kutsumi, Kengo Nagashima and Kazufumi Honda

Cancers 2020, 12(9), 2625; https://doi.org/10.3390/cancers12092625 - 14 Sep 2020

Cited by 15 | Viewed by 3092

Abstract

Apolipoprotein A2-ATQ/AT (apoA2-ATQ/AT) has been identified as a minimally invasive biomarker for detecting pancreatic cancer (PC) and high-risk (HR) individuals for PC. To establish an efficient enrichment strategy for HR, we carried out a plasma apoA2-ATQ/AT level-based prospective screening study among the general [...] Read more.

Apolipoprotein A2-ATQ/AT (apoA2-ATQ/AT) has been identified as a minimally invasive biomarker for detecting pancreatic cancer (PC) and high-risk (HR) individuals for PC. To establish an efficient enrichment strategy for HR, we carried out a plasma apoA2-ATQ/AT level-based prospective screening study among the general population. The subjects for the screening study were recruited at six medical check-up facilities in Japan between October 2015 and January 2017. We evaluated the positive predictive value (PPV) of the plasma apoA2-ATQ/AT level of ≤35 μg/mL for detecting PC and HR. Furthermore, we prospectively confirmed its diagnostic accuracy with another post-diagnosis population in a cross-sectional study. We enrolled 5120 subjects in experimental screening, with 84 subjects (1.3%) showing positive results for apoA2-ATQ/AT. Pancreatic abnormalities were recognized in 26 of the 84 subjects from imaging examinations. Pancreatic abnormalities detected included 1 PC and 15 HR abnormalities, such as cystic lesions including intraductal papillary mucinous neoplasm. The PPV of apoA2-ATQ/AT for detecting PC and HR was 33.3%. Moreover, a combination study with another cross-sectional study revealed that the area under the curve for apoA2-ATQ/AT to distinguish PC from healthy controls was 0.903. ApoA2-ATQ/AT has the potential to enrich PC and HR by increasing the diagnostic probability before imaging examinations. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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17 pages, 4490 KiB

Open AccessArticle

O-Glycan-Altered Extracellular Vesicles: A Specific Serum Marker Elevated in Pancreatic Cancer

by Takahiro Yokose, Yasuaki Kabe, Atsushi Matsuda, Minoru Kitago, Sachiko Matsuda, Miwa Hirai, Tomomi Nakagawa, Yohei Masugi, Takako Hishiki, Yuki Nakamura, Masahiro Shinoda, Hiroshi Yagi, Yuta Abe, Go Oshima, Shutaro Hori, Yutaka Nakano, Kazufumi Honda, Ayumi Kashiro, Chigusa Morizane, Satoshi Nara, Shojiro Kikuchi, Takahiko Shibahara, Makoto Itonaga, Masayuki Ono, Naoko Minegishi, Seizo Koshiba, Masayuki Yamamoto, Atsushi Kuno, Hiroshi Handa, Michiie Sakamoto, Makoto Suematsu and Yuko Kitagawa Show full author list Hide full author list

Cancers 2020, 12(9), 2469; https://doi.org/10.3390/cancers12092469 - 31 Aug 2020

Cited by 28 | Viewed by 5182

Abstract

Pancreatic cancer (PC) is among the most lethal malignancies due to an often delayed and difficult initial diagnosis. Therefore, the development of a novel, early stage, diagnostic PC marker in liquid biopsies is of great significance. In this study, we analyzed the differential [...] Read more.

Pancreatic cancer (PC) is among the most lethal malignancies due to an often delayed and difficult initial diagnosis. Therefore, the development of a novel, early stage, diagnostic PC marker in liquid biopsies is of great significance. In this study, we analyzed the differential glycomic profiling of extracellular vesicles (EVs) derived from serum (two cohorts including 117 PC patients and 98 normal controls) using lectin microarray. The glyco-candidates of PC-specific EVs were quantified using a high-sensitive exosome-counting system, ExoCounter. An absolute quantification system for altered glycan-containing EVs elevated in PC serum was established. EVs recognized by O-glycan-binding lectins ABA or ACA were identified as candidate markers by lectin microarray. Quantitative analyses using ExoCounter revealed that the ABA- or ACA-positive EVs were significantly increased in the culture of PC cell lines or in the serum of PC patients including carbohydrate antigen 19-9 negative patients with high area under curve values. The elevated numbers of EVs in PC serum returned to normal levels after pancreatectomy. Histological examination confirmed that the tumors stained with ABA/ACA. These specific EVs with O-glycans recognized by ABA/ACA are elevated in PC sera and can act as potential biomarkers in a liquid biopsy for PC patients screening. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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15 pages, 4746 KiB

Open AccessArticle

A Distinctive microRNA (miRNA) Signature in the Blood of Colorectal Cancer (CRC) Patients at Surgery

by Jessica Gasparello, Chiara Papi, Matteo Allegretti, Elena Giordani, Fabio Carboni, Settimio Zazza, Edoardo Pescarmona, Paolo Romania, Patrizio Giacomini, Chiara Scapoli, Roberto Gambari and Alessia Finotti

Cancers 2020, 12(9), 2410; https://doi.org/10.3390/cancers12092410 - 25 Aug 2020

Cited by 34 | Viewed by 4239

Abstract

Background: Liquid biopsy (LB) provides an examination of the peripheral blood of cancer patients for circulating tumor cells, cell-free nucleic acids and microRNAs (miRNAs) and is an established tool of precision medicine. Unlike most previous LB studies that focused on advanced metastatic colorectal [...] Read more.

Background: Liquid biopsy (LB) provides an examination of the peripheral blood of cancer patients for circulating tumor cells, cell-free nucleic acids and microRNAs (miRNAs) and is an established tool of precision medicine. Unlike most previous LB studies that focused on advanced metastatic colorectal cancer (CRC), we assessed miRNA dysregulation in blood samples obtained on the day of surgery from patients with primary CRC lesions but no clinical evidence of extra-colonic diffusion. In this study, plasma preparation included miRNAs associated to exosomes, but excluded large macrovesicles from the preparation. Methods: The miRNA profile in plasma isolated from a cohort of 35 CRC patients at the day of surgery was analyzed by Next Generation Sequencing (NGS) and further confirmed by droplet digital RT-PCR (dd-RT-PCR). Results: A miR-141-3p/miR-221-3p/miR-222-3p upregulation signature previously described in advanced CRC did not discriminate the analyzed early-CRC cohort from six tumor-free donors (Tf-D). In contrast, NGS-based miRNome analysis of a training cohort of five CRC and three tumor-free donors identified a novel, distinct nine miRNA signature comprising five up-regulated and four down-regulated miRNAs, six of which could be confirmed in the full CRC and tumor-free donor validation dataset by dd-RT-PCR. Additionally, a KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog) mutant status was correlated with the plasma content of three identified miRNAs. Conclusions: When the data obtained were comparatively evaluated, at least one of the miRNAs belonging to the signature list was found to be dysregulated in 34/35 (97.1%) of our early-CRC plasma samples. The miRNA list provides diagnostic markers as well as possible molecular targets for protocols focusing on “microRNA therapeutics”. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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14 pages, 4110 KiB

Open AccessArticle

Comprehensive Serum Glycopeptide Spectra Analysis Combined with Artificial Intelligence (CSGSA-AI) to Diagnose Early-Stage Ovarian Cancer

by Kazuhiro Tanabe, Masae Ikeda, Masaru Hayashi, Koji Matsuo, Miwa Yasaka, Hiroko Machida, Masako Shida, Tomoko Katahira, Tadashi Imanishi, Takeshi Hirasawa, Kenji Sato, Hiroshi Yoshida and Mikio Mikami

Cancers 2020, 12(9), 2373; https://doi.org/10.3390/cancers12092373 - 21 Aug 2020

Cited by 21 | Viewed by 3813

Abstract

Ovarian cancer is a leading cause of deaths among gynecological cancers, and a method to detect early-stage epithelial ovarian cancer (EOC) is urgently needed. We aimed to develop an artificial intelligence (AI)-based comprehensive serum glycopeptide spectra analysis (CSGSA-AI) method in combination with convolutional [...] Read more.

Ovarian cancer is a leading cause of deaths among gynecological cancers, and a method to detect early-stage epithelial ovarian cancer (EOC) is urgently needed. We aimed to develop an artificial intelligence (AI)-based comprehensive serum glycopeptide spectra analysis (CSGSA-AI) method in combination with convolutional neural network (CNN) to detect aberrant glycans in serum samples of patients with EOC. We converted serum glycopeptide expression patterns into two-dimensional (2D) barcodes to let CNN learn and distinguish between EOC and non-EOC. CNN was trained using 60% samples and validated using 40% samples. We observed that principal component analysis-based alignment of glycopeptides to generate 2D barcodes significantly increased the diagnostic accuracy (88%) of the method. When CNN was trained with 2D barcodes colored on the basis of serum levels of CA125 and HE4, a diagnostic accuracy of 95% was achieved. We believe that this simple and low-cost method will increase the detection of EOC. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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14 pages, 2402 KiB

Open AccessArticle

The Use of Artificial Intelligence in the Differentiation of Malignant and Benign Lung Nodules on Computed Tomograms Proven by Surgical Pathology

by Yung-Liang Wan, Patricia Wanping Wu, Pei-Ching Huang, Pei-Kwei Tsay, Kuang-Tse Pan, Nguyen Ngoc Trang, Wen-Yu Chuang, Ching-Yang Wu and ShihChung Benedict Lo

Cancers 2020, 12(8), 2211; https://doi.org/10.3390/cancers12082211 - 7 Aug 2020

Cited by 23 | Viewed by 5098

Abstract

The purpose of this work was to evaluate the performance of an existing commercially available artificial intelligence (AI) software system in differentiating malignant and benign lung nodules. The AI tool consisted of a vessel-suppression function and a deep-learning-based computer-aided-detection (VS-CAD) analyzer. Fifty patients [...] Read more.

The purpose of this work was to evaluate the performance of an existing commercially available artificial intelligence (AI) software system in differentiating malignant and benign lung nodules. The AI tool consisted of a vessel-suppression function and a deep-learning-based computer-aided-detection (VS-CAD) analyzer. Fifty patients (32 females, mean age 52 years) with 75 lung nodules (47 malignant and 28 benign) underwent low-dose computed tomography (LDCT) followed by surgical excision and the pathological analysis of their 75 nodules within a 3 month time frame. All 50 cases were then processed by the AI software to generate corresponding VS images and CAD outcomes. All 75 pathologically proven lung nodules were well delineated by vessel-suppressed images. Three (6.4%) of the 47 lung cancer cases, and 11 (39.3%) of the 28 benign nodules were ignored and not detected by the AI without showing a CAD analysis summary. The AI system/radiologists produced a sensitivity and specificity (shown in %) of 93.6/89.4 and 39.3/82.1 in distinguishing malignant from benign nodules, respectively. AI sensitivity was higher than that of radiologists, though not statistically significant (p = 0.712). Specificity obtained by the radiologists was significantly higher than that of the VS-CAD AI (p = 0.003). There was no significant difference between the malignant and benign lesions with respect to age, gender, pure ground-glass pattern, the diameter and location of the nodules, or nodules <6 vs. ≥6 mm. However, more part-solid nodules were proven to be malignant than benign (90.9% vs. 9.1%), and more solid nodules were proven to be benign than malignant (86.7% vs. 13.3%) with statistical significance (p = 0.001 and <0.001, respectively). A larger cohort and prospective study are required to validate the AI performance. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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12 pages, 651 KiB

Open AccessArticle

Detection of Colorectal Cancer and Advanced Adenoma by Liquid Biopsy (Decalib Study): The ddPCR Challenge

by Audelaure Junca, Gaëlle Tachon, Camille Evrard, Claire Villalva, Eric Frouin, Lucie Karayan-Tapon and David Tougeron

Cancers 2020, 12(6), 1482; https://doi.org/10.3390/cancers12061482 - 6 Jun 2020

Cited by 16 | Viewed by 3802

Abstract

Background: In most countries, participation in colorectal cancer (CRC) screening programs with the immunological fecal occult blood test (iFOBT) is low. Mutations of RAS and BRAF occur early in colorectal carcinogenesis and “liquid biopsy” allows detection of mutated circulating tumor DNA (ctDNA). This [...] Read more.

Background: In most countries, participation in colorectal cancer (CRC) screening programs with the immunological fecal occult blood test (iFOBT) is low. Mutations of RAS and BRAF occur early in colorectal carcinogenesis and “liquid biopsy” allows detection of mutated circulating tumor DNA (ctDNA). This prospective study aims to evaluate the performance of RAS and BRAF-mutated ctDNA in detecting CRC and advanced adenomas (AA). Methods: One hundred and thirty patients who underwent colonoscopy for suspicion of colorectal lesion were included and divided into four groups: 20 CRC, 39 AA, 31 non-advanced adenoma and/or hyperplastic polyp(s) (NAA) and 40 with no lesion. Mutated ctDNA was analyzed by droplet digital PCR. Results: ctDNA was detected in 45.0% of CRC, in 2.6% of AA and none of the NAA and “no-lesion” groups. All patients with stage II to IV mutated CRC had detectable ctDNA (n = 8/8). Among the mutated AA, only one patient had detectable ctDNA (4.3%), maybe due to limited technical sensitivity or to a low rate of ctDNA or even the absence ctDNA in plasma. Specificity and sensitivity of KRAS- and BRAF-mutated ctDNA for the detection of all CRC and AA were 100% and 16.9%, respectively. Conclusions: ctDNA had high sensitivity in detection of advanced mutated CRC but was unable to sensitively detect AA. ctDNA analysis was easy to perform and readily accepted by the population but requires combination with other circulating biomarkers before replacing iFOBT. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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17 pages, 2549 KiB

Open AccessArticle

Detecting Endometrial Cancer by Blood Spectroscopy: A Diagnostic Cross-Sectional Study

by Maria Paraskevaidi, Camilo L. M. Morais, Katherine M. Ashton, Helen F. Stringfellow, Rhona J. McVey, Neil A. J. Ryan, Helena O’Flynn, Vanitha N. Sivalingam, Sarah J. Kitson, Michelle L. MacKintosh, Abigail E. Derbyshire, Cecilia Pow, Olivia Raglan, Kássio M. G. Lima, Maria Kyrgiou, Pierre L. Martin-Hirsch, Francis L. Martin and Emma J. Crosbie

Cancers 2020, 12(5), 1256; https://doi.org/10.3390/cancers12051256 - 16 May 2020

Cited by 33 | Viewed by 10154

Abstract

Endometrial cancer is the sixth most common cancer in women, with a rising incidence worldwide. Current approaches for the diagnosis and screening of endometrial cancer are invasive, expensive or of moderate diagnostic accuracy, limiting their clinical utility. There is a need for cost-effective [...] Read more.

Endometrial cancer is the sixth most common cancer in women, with a rising incidence worldwide. Current approaches for the diagnosis and screening of endometrial cancer are invasive, expensive or of moderate diagnostic accuracy, limiting their clinical utility. There is a need for cost-effective and minimally invasive approaches to facilitate the early detection and timely management of endometrial cancer. We analysed blood plasma samples in a cross-sectional diagnostic accuracy study of women with endometrial cancer (n = 342), its precursor lesion atypical hyperplasia (n = 68) and healthy controls (n = 242, total n = 652) using attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy and machine learning algorithms. We show that blood-based infrared spectroscopy has the potential to detect endometrial cancer with 87% sensitivity and 78% specificity. Its accuracy is highest for Type I endometrial cancer, the most common subtype, and for atypical hyperplasia, with sensitivities of 91% and 100%, and specificities of 81% and 88%, respectively. Our large-cohort study shows that a simple blood test could enable the early detection of endometrial cancer of all stages in symptomatic women and provide the basis of a screening tool in high-risk groups. Such a test has the potential not only to differentially diagnose endometrial cancer but also to detect its precursor lesion atypical hyperplasia—the early recognition of which may allow fertility sparing management and cancer prevention. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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18 pages, 6696 KiB

Open AccessArticle

A Fluorescence-Based Wireless Capsule Endoscopy System for Detecting Colorectal Cancer

by Mohammad Wajih Alam, Seyed Shahim Vedaei and Khan A. Wahid

Cancers 2020, 12(4), 890; https://doi.org/10.3390/cancers12040890 - 6 Apr 2020

Cited by 21 | Viewed by 5226

Abstract

Wireless capsule endoscopy (WCE) has been widely used in gastrointestinal (GI) diagnosis that allows the physicians to examine the interior wall of the human GI tract through a pain-free procedure. However, there are still several limitations of the technology, which limits its functionality, [...] Read more.

Wireless capsule endoscopy (WCE) has been widely used in gastrointestinal (GI) diagnosis that allows the physicians to examine the interior wall of the human GI tract through a pain-free procedure. However, there are still several limitations of the technology, which limits its functionality, ultimately limiting its wide acceptance. Its counterpart, the wired endoscopic system is a painful procedure that demotivates patients from going through the procedure, and adversely affects early diagnosis. Furthermore, the current generation of capsules is unable to automate the detection of abnormality. As a result, physicians are required to spend longer hours to examine each image from the endoscopic capsule for abnormalities, which makes this technology tiresome and error-prone. Early detection of cancer is important to improve the survival rate in patients with colorectal cancer. Hence, a fluorescence-imaging-based endoscopic capsule that automates the detection process of colorectal cancer was designed and developed in our lab. The proof of concept of this endoscopic capsule was tested on porcine intestine and liquid phantom. The proposed WCE system offers great possibilities for future applicability in selective and specific detection of other fluorescently labelled cancers. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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12 pages, 1676 KiB

Open AccessArticle

Urine Endocannabinoids as Novel Non-Invasive Biomarkers for Bladder Cancer at Early Stage

by Riccardo Vago, Alessandro Ravelli, Arianna Bettiga, Silvana Casati, Giovanni Lavorgna, Fabio Benigni, Andrea Salonia, Francesco Montorsi, Marica Orioli, Pierangela Ciuffreda and Roberta Ottria

Cancers 2020, 12(4), 870; https://doi.org/10.3390/cancers12040870 - 3 Apr 2020

Cited by 18 | Viewed by 2974

Abstract

Due to the involvement of the endocannabinoid system (ECS) in cancer onset and progression and the less studied connection between ECS and bladder cancer, here an evaluation of the ECS modifications associated with bladder cancer is reported. Urine samples were collected from healthy [...] Read more.

Due to the involvement of the endocannabinoid system (ECS) in cancer onset and progression and the less studied connection between ECS and bladder cancer, here an evaluation of the ECS modifications associated with bladder cancer is reported. Urine samples were collected from healthy volunteers and patients with bladder cancer at different grades. Endocannabinoids (ECs) and N-acylethanolamides (NAEs) were quantified by HPLC-MS/MS and results normalized for creatinine content. An increase in the urine concentrations of four ECs and NAEs analyzed was observed with a statistically significant increase in the arachidonoylethanolamide (AEA) and stearoylethanoamide (SEA) associated with bladder cancer. Receiver operating characteristic curves built with AEA and SEA data allowed the selection of 160 pg/mL for SEA (area under the curve (AUC) = 0.91, Selectivity (SE) 94%, Specificity (SP) 45%) and 8 pg/mL for AEA (AUC = 0.85, SE 94%, SP 61%) as the best cut-off values. Moreover, data from bladder cancer samples at different grades were derived from The Cancer Genome Atlas, and the expressions of thirteen different components of the “endocannabinoidome” were analyzed. Statistical analysis highlights significant variations in the expression of three enzymes involved in EC and NAE turnover in bladder cancer. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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12 pages, 993 KiB

Open AccessFeature PaperArticle

Multi-Reader Multi-Case Study for Performance Evaluation of High-Risk Thyroid Ultrasound with Computer-Aided Detection

by Ming-Hsun Wu, Kuen-Yuan Chen, Shyang-Rong Shih, Ming-Chih Ho, Hao-Chih Tai, King-Jen Chang, Argon Chen and Chiung-Nien Chen

Cancers 2020, 12(2), 373; https://doi.org/10.3390/cancers12020373 - 6 Feb 2020

Cited by 15 | Viewed by 4977

Abstract

Physicians use sonographic characteristics as a reference for the possible diagnosis of thyroid cancers. The purpose of this study was to investigate whether physicians were more effective in their tentative diagnosis based on the information provided by a computer-aided detection (CAD) system. A [...] Read more.

Physicians use sonographic characteristics as a reference for the possible diagnosis of thyroid cancers. The purpose of this study was to investigate whether physicians were more effective in their tentative diagnosis based on the information provided by a computer-aided detection (CAD) system. A computer compared software-defined and physician-adjusted tumor loci. A multicenter, multireader, and multicase (MRMC) study was designed to compare clinician performance without and with the use of CAD. Interobserver variability was also analyzed. Excellent, satisfactory, and poor segmentations were observed in 25.3%, 58.9%, and 15.8% of nodules, respectively. There were 200 patients with 265 nodules in the study set. Nineteen physicians scored the malignancy potential of the nodules. The average area under the curve (AUC) of all readers was 0.728 without CAD and significantly increased to 0.792 with CAD. The average standard deviation of the malignant potential score significantly decreased from 18.97 to 16.29. The mean malignant potential score significantly decreased from 35.01 to 31.24 for benign cases. With the CAD system, an additional 7.6% of malignant nodules would be suggested for further evaluation, and biopsy would not be recommended for an additional 10.8% of benign nodules. The results demonstrated that applying a CAD system would improve clinicians’ interpretations and lessen the variability in diagnosis. However, more studies are needed to explore the use of the CAD system in an actual ultrasound diagnostic situation where much more benign thyroid nodules would be seen. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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Review

Jump to: Research, Other

15 pages, 1340 KiB

Open AccessReview

Non-Invasive Diagnostic System Based on Light for Detecting Early-Stage Oral Cancer and High-Risk Precancerous Lesions—Potential for Dentistry

by Seiko Tatehara and Kazuhito Satomura

Cancers 2020, 12(11), 3185; https://doi.org/10.3390/cancers12113185 - 29 Oct 2020

Cited by 13 | Viewed by 4249

Abstract

Oral health promotion and examinations have contributed to the early detection of oral cancer and oral potentially malignant disorders, leading to the adaptation of minimally invasive therapies and subsequent improvements in the prognosis/maintenance of the quality of life after treatments. However, the accurate [...] Read more.

Oral health promotion and examinations have contributed to the early detection of oral cancer and oral potentially malignant disorders, leading to the adaptation of minimally invasive therapies and subsequent improvements in the prognosis/maintenance of the quality of life after treatments. However, the accurate detection of early-stage oral cancer and oral epithelial dysplasia is particularly difficult for conventional oral examinations because these lesions sometimes resemble benign lesions or healthy oral mucosa tissues. Although oral biopsy has been considered the gold standard for accurate diagnosis, it is deemed invasive for patients. For this reason, most clinicians are looking forward to the development of non-invasive diagnostic technologies to detect and distinguish between cancerous and benign lesions. To date, several non-invasive adjunctive fluorescence-based detection systems have improved the accuracy of the detection and diagnosis of oral mucosal lesions. Autofluorescence-based systems can detect lesions as a loss of autofluorescence through irradiation with blue-violet lights. Photodynamic diagnosis using 5-aminolevulinic acid (ALA-PDD) shows the presence of very early oral cancers and oral epithelial dysplasia as a red fluorescent area. In this article, currently used fluorescence-based diagnostic methods are introduced and discussed from a clinical point of view. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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30 pages, 2606 KiB

Open AccessReview

The Diagnostic and Prognostic Value of a Liquid Biopsy for Esophageal Cancer: A Systematic Review and Meta-Analysis

by Daisuke Matsushita, Takaaki Arigami, Keishi Okubo, Ken Sasaki, Masahiro Noda, Yoshiaki Kita, Shinichiro Mori, Yoshikazu Uenosono, Takao Ohtsuka and Shoji Natsugoe

Cancers 2020, 12(10), 3070; https://doi.org/10.3390/cancers12103070 - 21 Oct 2020

Cited by 9 | Viewed by 3599

Abstract

Esophageal cancer is among the most aggressive diseases, and circulating tumor cells (CTCs) have been recognized as novel biomarkers for various cancers over the past two decades, including esophageal cancer. CTCs might provide crucial clinical information for predicting cancer prognosis, monitoring therapeutic responses [...] Read more.

Esophageal cancer is among the most aggressive diseases, and circulating tumor cells (CTCs) have been recognized as novel biomarkers for various cancers over the past two decades, including esophageal cancer. CTCs might provide crucial clinical information for predicting cancer prognosis, monitoring therapeutic responses or recurrences, or elucidating the mechanism of metastasis. The isolation of CTCs is among the applications of a “liquid biopsy”. There are various technologies for liquid biopsies, and they are classified into two main methods: cytometric or non-cytometric techniques. Here, we review a total of 57 eligible articles to summarize various technologies for the use of a liquid biopsy in esophageal cancer and perform a meta-analysis to assess the clinical utility of liquid biopsies as a prognostic and diagnostic biomarker technique. For prognostic evaluation, the pooled hazard ratio in the cytometric assay is relatively higher than that of the non-cytometric assay. On the other hand, a combination of multiple molecules, using a non-cytometric assay, might be a favorable biomarker technique for the early diagnosis of esophageal cancer. Although determining strong evidence for a biomarker by using a liquid biopsy is still challenging, our meta-analysis might be a milestone for the future development of liquid biopsies in use with esophageal cancer. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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28 pages, 1619 KiB

Open AccessReview

EVs as Potential New Therapeutic Tool/Target in Gastrointestinal Cancer and HCC

by Artur Słomka, Tudor Mocan, Bingduo Wang, Iuliana Nenu, Sabine K. Urban, Maria A. Gonzalez-Carmona, Ingo G. H. Schmidt-Wolf, Veronika Lukacs-Kornek, Christian P. Strassburg, Zeno Spârchez and Miroslaw Kornek

Cancers 2020, 12(10), 3019; https://doi.org/10.3390/cancers12103019 - 17 Oct 2020

Cited by 18 | Viewed by 4455

Abstract

For more than a decade, extracellular vesicles (EVs) have been in focus of science. Once thought to be an efficient way to eliminate undesirable cell content, EVs are now well-accepted as being an important alternative to cytokines and chemokines in cell-to-cell communication route. [...] Read more.

For more than a decade, extracellular vesicles (EVs) have been in focus of science. Once thought to be an efficient way to eliminate undesirable cell content, EVs are now well-accepted as being an important alternative to cytokines and chemokines in cell-to-cell communication route. With their cargos, mainly consisting of functional proteins, lipids and nucleic acids, they can activate signalling cascades and thus change the phenotype of recipient cells at local and systemic levels. Their substantial role as modulators of various physiological and pathological processes is acknowledged. Importantly, more and more evidence arises that EVs play a pivotal role in many stages of carcinogenesis. Via EV-mediated communication, tumour cells can manipulate cells from host immune system or from the tumour microenvironment, and, ultimately, they promote tumour progression and modulate host immunity towards tumour’s favour. Additionally, the role of EVs in modulating resistance to pharmacological and radiological therapy of many cancer types has become evident lately. Our understanding of EV biology and their role in cancer promotion and drug resistance has evolved considerably in recent years. In this review, we specifically discuss the current knowledge on the association between EVs and gastrointestinal (GI) and liver cancers, including their potential for diagnosis and treatment. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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17 pages, 5710 KiB

Open AccessReview

Non-Invasive Early Molecular Detection of Gastric Cancers

by Hiroyuki Yamamoto, Yoshiyuki Watanabe, Yoshinori Sato, Tadateru Maehata and Fumio Itoh

Cancers 2020, 12(10), 2880; https://doi.org/10.3390/cancers12102880 - 7 Oct 2020

Cited by 24 | Viewed by 5157

Abstract

Gastric cancer (GC) is a significant source of global cancer death with a high mortality rate, because the majority of patients with GC are diagnosed at a late stage, with limited therapeutic choices and poor outcomes. Therefore, development of minimally invasive or noninvasive [...] Read more.

Gastric cancer (GC) is a significant source of global cancer death with a high mortality rate, because the majority of patients with GC are diagnosed at a late stage, with limited therapeutic choices and poor outcomes. Therefore, development of minimally invasive or noninvasive biomarkers which are specific to GC is crucially needed. The latest advancements in the understanding of GC molecular landscapes and molecular biological methods have accelerated attempts to diagnose GC at an early stage. Body fluids, including peripheral blood, saliva, gastric juice/wash, urine, and others, can be a source of biomarkers, offering new methods for the early detection of GC. Liquid biopsy-based methods using circulating sources of cancer nucleic acids could also be considered as alternative strategies. Moreover, investigating gastric juices/washes could represent an alternative for the detection of GC via invasive biopsy. This review summarizes recently reported biomarkers based on DNA methylation, microRNA, long noncoding RNA, circular RNA, or extracellular vesicles (exosomes) for the detection of GC. Although the majority of studies have been conducted to detect these alterations in advanced-stage GC and only a few in population studies or early-stage GC, some biomarkers are potentially valuable for the development of novel approaches for an early noninvasive detection of GC. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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21 pages, 750 KiB

Open AccessReview

Use of Biomarkers and Imaging for Early Detection of Pancreatic Cancer

by Shingo Kato and Kazufumi Honda

Cancers 2020, 12(7), 1965; https://doi.org/10.3390/cancers12071965 - 19 Jul 2020

Cited by 35 | Viewed by 5350

Abstract

Pancreatic cancer remains one of the deadliest cancers worldwide, and it is typically diagnosed late, with a poor prognosis. Early detection is the most important underlying factor for improving the prognosis of pancreatic cancer patients. One of the most effective strategies for detecting [...] Read more.

Pancreatic cancer remains one of the deadliest cancers worldwide, and it is typically diagnosed late, with a poor prognosis. Early detection is the most important underlying factor for improving the prognosis of pancreatic cancer patients. One of the most effective strategies for detecting cancers at an early stage is screening of the general population. However, because of the low incidence of pancreatic cancer in the general population, the stratification of subjects who need to undergo further examinations by invasive and expensive modalities is important. Therefore, minimally invasive modalities involving biomarkers and imaging techniques that would facilitate the early detection of pancreatic cancer are highly needed. Multiple types of new blood biomarkers have recently been developed, including unique post-translational modifications of circulating proteins, circulating exosomes, microRNAs, and circulating tumor DNA. We previously reported that circulating apolipoprotein A2 undergoes unique processing in the bloodstream of patients with pancreatic cancer and its precancerous lesions. Additionally, we recently demonstrated a new method for measuring pancreatic proton density in the fat fraction using a fat–water magnetic resonance imaging technique that reflects pancreatic steatosis. In this review, we describe recent developments in potential biomarkers and imaging modalities for the early detection and risk stratification of pancreatic cancer, and we discuss current strategies for implementing screening programs for pancreatic cancer. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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19 pages, 715 KiB

Open AccessEditor’s ChoiceReview

Fourier Transform Infrared Spectroscopy as a Cancer Screening and Diagnostic Tool: A Review and Prospects

by Kar-Yan Su and Wai-Leng Lee

Cancers 2020, 12(1), 115; https://doi.org/10.3390/cancers12010115 - 1 Jan 2020

Cited by 122 | Viewed by 11533

Abstract

Infrared spectroscopy has long been used to characterize chemical compounds, but the applicability of this technique to the analysis of biological materials containing highly complex chemical components is arguable. However, recent advances in the development of infrared spectroscopy have significantly enhanced the capacity [...] Read more.

Infrared spectroscopy has long been used to characterize chemical compounds, but the applicability of this technique to the analysis of biological materials containing highly complex chemical components is arguable. However, recent advances in the development of infrared spectroscopy have significantly enhanced the capacity of this technique in analyzing various types of biological specimens. Consequently, there is an increased number of studies investigating the application of infrared spectroscopy in screening and diagnosis of various diseases. The lack of highly sensitive and specific methods for early detection of cancer has warranted the search for novel approaches. Being more simple, rapid, accurate, inexpensive, non-destructive and suitable for automation compared to existing screening, diagnosis, management and monitoring methods, Fourier transform infrared spectroscopy can potentially improve clinical decision-making and patient outcomes by detecting biochemical changes in cancer patients at the molecular level. Besides the commonly analyzed blood and tissue samples, extracellular vesicle-based method has been gaining popularity as a non-invasive approach. Therefore, infrared spectroscopic analysis of extracellular vesicles could be a useful technique in the future for biomedical applications. In this review, we discuss the potential clinical applications of Fourier transform infrared spectroscopic analysis using various types of biological materials for cancer. Additionally, the rationale and advantages of using extracellular vesicles in the spectroscopic analysis for cancer diagnostics are discussed. Furthermore, we highlight the challenges and future directions of clinical translation of the technique for cancer. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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Other

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9 pages, 368 KiB

Open AccessCommentary

Triage May Improve Selection to Colonoscopy and Reduce the Number of Unnecessary Colonoscopies

by Mathias M. Petersen, Linnea Ferm, Jakob Kleif, Thomas B. Piper, Eva Rømer, Ib J. Christensen and Hans J. Nielsen

Cancers 2020, 12(9), 2610; https://doi.org/10.3390/cancers12092610 - 12 Sep 2020

Cited by 9 | Viewed by 2071

Abstract

Implementation of population screening for colorectal cancer by direct colonoscopy or follow-up colonoscopy after a positive fecal blood test has challenged the overall capacity of bowel examinations. Certain countries are facing serious colonoscopy capacity constraints, which have led to waiting lists and long [...] Read more.

Implementation of population screening for colorectal cancer by direct colonoscopy or follow-up colonoscopy after a positive fecal blood test has challenged the overall capacity of bowel examinations. Certain countries are facing serious colonoscopy capacity constraints, which have led to waiting lists and long time latency of follow-up examinations. Various options for improvement are considered, including increased cut-off values of the fecal blood tests. Results from major clinical studies of blood-based, cancer-associated biomarkers have, however, led to focus on a Triage concept for improved selection to colonoscopy. The Triage test may include subject age, concentration of hemoglobin in a feces test and a combination of certain blood-based cancer-associated biomarkers. Recent results have indicated that Triage may reduce the requirements for colonoscopy by around 30%. Such results may be advantageous for the capacity, the healthcare budgets and in particular, the subjects, who do not need an unnecessary, unpleasant and risk-associated bowel examination. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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11 pages, 827 KiB

Open AccessPerspective

Biobanking in Molecular Biomarker Research for the Early Detection of Cancer

by Kim Lommen, Selena Odeh, Chiel C. de Theije and Kim M. Smits

Cancers 2020, 12(4), 776; https://doi.org/10.3390/cancers12040776 - 25 Mar 2020

Cited by 17 | Viewed by 5746

Abstract

Although population-wide screening programs for several cancer types have been implemented in multiple countries, screening procedures are invasive, time-consuming and often perceived as a burden for patients. Molecular biomarkers measurable in non-invasively collected samples (liquid biopsies) could facilitate screening, as they could have [...] Read more.

Although population-wide screening programs for several cancer types have been implemented in multiple countries, screening procedures are invasive, time-consuming and often perceived as a burden for patients. Molecular biomarkers measurable in non-invasively collected samples (liquid biopsies) could facilitate screening, as they could have incremental value on early diagnosis of cancer, but could also predict prognosis or monitor treatment response. Although the shift towards biomarkers from liquid biopsies for early cancer detection was initiated some time ago, there are many challenges that hamper the development of such biomarkers. One of these challenges is large-scale validation that requires large prospectively collected biobanks with liquid biopsies. Establishing those biobanks involves several considerations, such as standardization of sample collection, processing and storage within and between biobanks. In this perspective, we will elaborate on several issues that need to be contemplated in biobanking, both in general and for certain specimen types specifically, to be able to facilitate biomarker validation for early detection of cancer. Full article

(This article belongs to the Special Issue Non-Invasive Early Detection of Cancers)

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