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Cancerous cells forming a lump in the pancreatic tissue.
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Detecting Pancreatic Cancer: Implementing Novel Methods

Introduction

Pancreatic cancer (PC) is a formidable global health challenge, outranking many other cancers worldwide [1]. Its high mortality rate is closely linked to the lack of noticeable symptoms until the disease has advanced, making early detection and intervention exceedingly challenging [5]. However, recent advancements in diagnostic methods, medical therapies, and other contributing factors have provided avenues for detecting pancreatic cancer in its early stages. The urgency to comprehend and mitigate the progression of this devastating disease is undermined by its alarming incidence and mortality rates.

With the ongoing research and developments in the field of pancreatic cancer, researchers explore various approaches and breakthroughs that offer insights into reducing the progression of this disease. The primary focus is on understanding the mechanisms of pancreatic cancer progression, identifying strategies for early detection, and highlighting medical techniques used in the later stages of the disease [2]. By creating a comprehensive understanding of the latest findings, this literature review aims to shed light on the potential interventions and advancements that can aid in the battle against pancreatic cancer.

With an early prognosis, the implementation of newly developed techniques can be emphasized, aiming to identify and eliminate cancer cells before they have a chance to replicate and metastasize. By providing an overview of the research and contributions in the field of research, this literature review serves as a tool for individuals affected by pancreatic cancer. It offers valuable insights into the ongoing efforts to combat this devastating disease, foster early detection, and improve patient outcomes.

Prognosis

Amongst cancers pertaining to solid tumors, Ehlen L. et al. explain that pancreatic cancer has the worst prognosis, with a five-year survival rate of less than 9 % [2]. Surgical resection is the only potentially curative treatment, but it is limited to a restricted number of patients due to late-stage diagnosis and associated risks [1]. Moreover, surgical interventions continue to carry a notable risk of complications in the postoperative phase, and alternative treatment methods have yielded discouraging results. The tumor stage plays a vital role in determining the prognosis of cancer. After undergoing surgical resection, patients with different stages of cancer experienced varying median survival durations [2]. Various factors impact the prognosis of pancreatic ductal adenocarcinoma (PDAC). These include surgical status, tumor grading, lymphatic invasion, and preoperative/postoperative CA 19-9 serum levels [1]. The stages of cancer reflect the disease progression and influence the patient's recovery potential and prognosis. Analyzing statistical data on early prognosis enables a more precise assessment of potential outcomes for individuals in different stages of pancreatic cancer, ultimately enhancing their chances of survival.

In Vitro Modeling of Pancreatic Cells

Pancreatic ductal adenocarcinoma (PDAC) can be effectively studied through in vitro modeling of pancreatic cancer cells, providing valuable insights into their behavior and characteristics, as well as aiding in the development of targeted therapies. In a study conducted by Ehlen, L. et al., an in vitro model was created using tissue samples collected from tumor cells, enabling the replication of cancer cells for further analysis [2]. In vitro models offer a controlled and reproducible environment for researchers to investigate the behaviors and characteristics of PDAC cells [2]. This approach proves significant as it helps identify molecular targets for potential therapeutics and assesses the efficacy of drug candidates in preclinical settings, as emphasized by Feldmann [10]. Such models allow for a deeper understanding of cancer cells in different environments and facilitate the development of novel therapeutic strategies. Ethical considerations make in vitro techniques essential, as using patients as experimental subjects is not appropriate [1]. The utilization of these research approaches contributes to advancing the understanding of PDAC and holds promise for improving patient outcomes in the future.

Enhanced Imaging Techniques for Early Diagnosis

Enhanced imaging techniques play a crucial role in the early diagnosis of pancreatic cancer. Yamashita Y. et al. conducted a study to assess the diagnostic capabilities of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) in comparison to multidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI) for the early detection of small pancreatic cancer (PC) [3]. The study included patients with a pancreatic solid lesion measuring ≤20 mm, who underwent surgery after undergoing evaluation with all three imaging modalities (CH-EUS, MDCT, and MRI). The three modalities used in this research are the most common, with CH-EUS being the superior form of enhanced imaging used to date to detect lesions 20 mm or smaller. There are areas of this study that give statistical significance as to why CH-EUS is a superior Imaging technique for early diagnostics of PDAC.

The usage of CH-EUS has significantly higher rates of adequate sampling when observing pancreatic lesions. The researchers support this finding when investigating the efficacy of endoscopic ultrasound-guided fine-needle aspiration with contrast-enhanced harmonic imaging (EUS-FNA-CHI) compared to endoscopic ultrasound-guided fine-needle aspiration with fundamental B mode imaging (EUS-FNA-FBI) for diagnosing solid pancreatic lesions [11]. The researchers enrolled consecutive patients with solid pancreatic lesions and compared the accuracy rate for diagnosing pancreatic lesions and the rate of adequate sampling for histological evaluation between the two techniques. They also performed subgroup analyses based on lesion characteristics observed on contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) [11]. CH-EUS enables improved observation of pancreatic lesions and helps identify the target for EUS-FNA among different pathological areas of the lesions, especially for lesions larger than 15 mm [10,11]. This study suggests that EUS-FNA-CHI may improve the diagnostic yield of EUS-FNA for solid pancreatic lesions.

Low-Cost Paper-Based Immunosensor for Early Detection 

Figure 1
Figure 1: Schematic of Paper-based Immunosensor

With no definitive route for detecting pancreatic cancer, novel techniques are synthesized to find potential pathways that can lead to early detection, as well as quantify the cancer using biomarkers. The imperative objective of both developing and developed regions is to advance the creation of precise and dependable point-of-care (POC) devices that can sensitively detect and monitor cancer at an early stage [9]. In their study, Prasad, K. et al. introduced a novel approach utilizing paper-based electrodes (PPEs) to develop a disposable and affordable paper-based immunosensor. This immunosensor enabled rapid quantitative detection of pancreatic cancer at an early stage, utilizing a newly identified biomarker called pseudopodium-enriched atypical kinase one, SGK269 (PEAK1) [4]. Incorporating an immunosensor allows the researchers to trace PDAC biomarker, PEAK1. PEAK1 bio marker exploits areas of potential cancer, which can then be quantified to express the progression of PDAC. 

The previously mentioned electrochemical detection method, when combined with gold nanoparticles, achieves a heightened level of detection sensitivity. Accurate detection is crucial in pancreatic cancer diagnosis. The introduction of gold particles through the immunoreaction enhances the electroactive surface area on the graphene oxide (GO) electrode, thereby improving electrode conductivity and electron transfer [4]. Supporting this innovative approach, Xiao G. et al. demonstrated the effectiveness of paper-based immunosensors combined with gold nanoparticles for the detection of various cancer biomarkers [12]. The researchers successfully utilized the unique properties of gold nanoparticles, such as their high surface area-to-volume ratio and excellent conductivity, to enhance the performance of the immunosensor [4,12]. The integration of gold nanoparticles enabled ultrasensitive detection of cancer biomarkers, these findings provide further evidence of the potential of gold nanoparticle-enhanced paper-based immunosensors for sensitive and reliable cancer detection.

The integration of gold nanoparticles enhances the electroactive surface area and conductivity of the immunosensor, allowing for improved detection sensitivity. The visual qualitative changes exhibited by the gold nanoparticles offer a convenient and accessible method for initial screening, while the electrochemical detection method provides more precise and quantitative data [4,12]. 

Label-Free Characterization of Exosomes for Detection

Nanomedicine exploits the unique properties and interactions of nanoscale materials and devices to diagnose, treat, and prevent diseases at the molecular level. According to Carmicheal, J. et al., the current approaches employed in the assessment of tumor diagnosis and prognosis using exosomes have limitations that restrict their diagnostic potential. To address this, Raman spectroscopy, a vibrational technique, is utilized. This technique involves measuring photons that are scattered inelastically after a sample interacts with a monochromatic laser light [5]. This technique can be used to analyze samples, being label-free and non-destructive, meaning it can be done in vivo with no undue risk to the patient. Raman spectroscopy will provide the ability to express exomes that are representative of pancreatic cells. 

Detection of Early-Stage Pancreatic Cancer in Circulating DNA

Figure 2
Figure 2: Epigenetic Alterations in PDAC

In their investigation, Guler, G. et al. introduce a non-invasive technique to detect pancreatic ductal adenocarcinoma (PDAC) by examining alterations in 5-hydroxymethylcytosine (5hmC) levels in circulating cell-free DNA derived from a PDAC group. The study reveals distinctive changes in hydroxy methylation within multiple genes, with significant modifications identified in genes linked to pancreatic development, function, and cancer pathogenesis [6]. 

Notably, the researchers observe a widespread reduction in 5hmC levels, as indicated by a decrease in the number of peaks, which aligns with earlier investigations on tissue samples, highlighting the impact of this epigenetic mark on pancreatic ductal adenocarcinoma (PDAC) [6]. 

Fujikura, K. et al. describe 5-hydroxymethylcytosine (5hmC) as an epigenetic DNA modification generated through the enzymatic pathway mediated by ten-eleven translocation (TET) enzymes, this modification is intricately associated with gene activation [7]. Expanding upon this finding, the study identifies a significant decrease in the expression of nuclear TET1 in both precancerous lesions and invasive PDACs compared to normal ductal epithelium, emphasizing the relevance of this discovery [7]. The non-invasive detection of PDAC by assessing the 5-hydroxymethylcytosine (5hmC) levels in circulating cell-free DNA provides a promising non-invasive approach for detecting pancreatic ductal adenocarcinoma (PDAC) and offers valuable insights into the epigenetic landscape and gene expression alterations associated with PDAC pathogenesis.

Tumor-Specific Fluorescence-Guided Surgery 

Tumor-specific fluorescence-guided surgery utilizing panitumumab-IRDye800CW presents a promising approach for the early detection of pancreatic ductal adenocarcinoma (PDAC) by providing enhanced visualization of tumor margins and metastatic lesions, including small peritoneal metastases and visually occult cancer [8]. Timely diagnosis is crucial due to the advanced stage at which PDAC is often detected, and early identification and resection of tumors can potentially improve patient outcomes and increase curative treatment options [1]. The demonstrated safety and feasibility of panitumumab-IRDye800CW support its potential integration into routine clinical practice for improved management of PDAC. A single-center study by Lu G et al. confirms the safety and feasibility of intraoperative panitumumab-IRDye800CW use, enhancing surgical outcomes through real-time visualization of primary tumors, peritoneal metastases, and metastatic lymph nodes, without reporting significant adverse events [8]. These findings highlight the potential of tumor-specific intraoperative imaging to improve patient selection and enhance surgical precision in PDAC. 

Conclusion

In conclusion, pancreatic cancer is a major global health challenge with a high mortality rate. Early detection and intervention are difficult due to the absence of noticeable symptoms until the disease reaches an advanced stage. However, recent advancements in diagnostic methods, coupled with medical therapies and other factors, offer hope for catching pancreatic cancer in its early stages. The prognosis of pancreatic cancer is poor, with a five-year survival rate of less than 9%. Surgical resection is the best curative treatment, but it is limited to a restricted number of patients due to late-stage diagnosis and associated risks. 

In vitro modeling of pancreatic cancer cells allows researchers to study their behavior and characteristics in a controlled environment, aiding in the development of targeted therapeutic strategies. Enhanced imaging techniques, such as contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS), offer superior diagnostic capabilities for early detection of small pancreatic cancer lesions. Novel approaches, like low-cost paper-based immunosensors and label-free characterization of exosomes using Raman spectroscopy, show potential for early detection and personalized treatment. These advancements contribute to improved strategies for early diagnosis and management of pancreatic cancer. Tumor-specific fluorescence-guided surgery using imaging agents shows promise for early diagnosis and improved management of PDAC. This technique enhances visualization of tumor margins, metastatic lymph nodes, and peritoneal metastases, enabling real-time detection and surgical precision. 

Overall, these research findings and developments provide valuable insights into understanding the progression of pancreatic cancer, strategies for early detection, and medical techniques used in later stages. They offer hope for improving patient outcomes and reducing the impact of this deadly disease.

References

  1. Tonini V., Zanni M. Pancreatic Cancer in 2021: What you need to know to win. 2021. 10.3748/wjg.v27.i35.5851
  2. Ehlen, L., Arndt, J., Treue, D. et al. Novel methods for in vitro modeling of pancreatic cancer reveal important aspects for successful primary cell culture. BMC Cancer 2020. https://doi.org/10.1186/s12885-020-06929-8
  3. Yamashita, Y.; Tanioka, K.; Kawaji, Y.; Tamura, T.; Nuta, J.; Hatamaru, K.; Itonaga, M.; Yoshida, T.; Ida, Y.; Maekita, T.; Iguchi, M.; Terada, M.; Sonomura, T.; Hirono, S.; Okada, K.-I.; Kawai, M.; Yamaue, H.; Kitano, M. 2020 Utility of Contrast-Enhanced Harmonic Endoscopic Ultrasonography for Early Diagnosis of Small Pancreatic Cancer. Diagnostics. https://doi.org/10.3390/diagnostics10010023
  4. Prasad K, Cao X, Gao N, Jin Q, Sanjay S, Henao-Pabon G, Li X. 2020. A low-cost nanomaterial-based electrochemical immunosensor on paper for high-sensitivity early detection of pancreatic cancer, Sensors and Actuators B: Chemical. https://doi.org/10.1016/j.snb.2019.127516.
  5. Carmicheal J, Hayashi C, Huang X, Liu L, Lu Y, Krasnoslobodtsev A, Lushnikov A, Kshirsagar P, Patel A, Jain M, Lyubchenko Y, Lu Y, Batra S, Kaur S. 2019. Label-free characterization of exosome via surface enhanced Raman spectroscopy for the early detection of pancreatic cancer, Nanomedicine: Nanotechnology, Biology and Medicine. https://doi.org/10.1016/j.nano.2018.11.008.
  6. Guler G, Ning Y, Ku CJ. et al. 2020. Detection of early stage pancreatic cancer using 5-hydroxymethylcytosine signatures in circulating cell free DNA. https://doi.org/10.1038/s41467-020-18965-w
  7. Fujikura K, Alruwaii ZI, Haffner MC, Trujillo MA, Roberts NJ, Hong SM, Macgregor-Das A, Goggins MG, Roy S, Meeker AK, Ding D, Wright M, He J, Hruban RH, Wood LD. 2021. Downregulation of 5-hydroxymethylcytosine is an early event in pancreatic tumorigenesis. doi: 10.1002/path.5682
  8. Lu G, Berg N, Martin B, Nishio N, Hart Z, Keulen S, Fakurnejad S, Chirita S, Raymundo R, Yi G, Zhou Q, Fisher G, Rosenthal E, Poultsides G. 2020. Tumour-specific fluorescence-guided surgery for pancreatic cancer using panitumumab-IRDye800CW: a phase 1 single-centre, open-label, single-arm, dose-escalation study. The Lancet Gastroenterology & Hepatology. https://doi.org/10.1016/S2468-1253(20)30088-1.
  9. Yen Y, Chao C, Yeh Y. 2020. A Graphene-PEDOT:PSS Modified Paper-Based Aptasensor for Electrochemical Impedance Spectroscopy Detection of Tumor Marker. https://doi.org/10.3390/s20051372
  10. Feldmann G, Rauenzahn S, Maitra A. 2009. In vitro models of pancreatic cancer for translational oncology research. https://doi.org/10.1517/17460440902821657
  11.  Itonaga M, Kitano M, Kojima F, Hatamaru K, Yamashita Y, Tamura T, Nuta J, Kawaji Y, Shimokawa T, Tanioka K, Murata S. 2020. The usefulness of EUS-FNA with contrast-enhanced harmonic imaging of solid pancreatic lesions: A prospective study. https://doi.org/10.1111/jgh.15144
  12. Xiao G, Ge H, Yang Q, Zhang Z, Cheng L, Cao S, Ji J, Zhang J, Yue Z. 2022. Light-addressable photoelectrochemical sensors for multichannel detections of GPC1, CEA and GSH and its applications in early diagnosis of pancreatic cancer. https://doi.org/10.1016/j.snb.2022.132663

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