**6. Therapeutics**

#### **6.1. Celiac plexus neurolysis**

The first reported use of EUS-guided celiac plexus neurolysis (EUS-CPN) was published by Wiersema in 1996. EUS-CPN was performed on 30 patients with celiac plexus neuropathy; 25 with PC, and 5 with other intraabdominal malignancies. This single-arm study demonstrated efficacy in a mild to moderate reduction in pain scores at 2, 4, 8, and 12 weeks post-procedure (1–10 pain scale 6.1 +/− 3.1 versus 4.8 +/− 2.0, p = 0.004) [40]. Complications were minor and transient (diarrhoea in four patients).

Although no randomised clinical trial has been performed to compare the relative efficacy and safety of CPN via percutaneous versus endoscopic approach, a Cochrane Review of 102 studies concluded that CPN by any modality was associated with reduced pain at 4 weeks (mean difference in visual analogue scale (VAS) −0.42, 95% CI −0.70 to −0.13, p = 0.004). This less than one point improvement of VAS score begs the question of whether this is clinicallysignificant; coupling this data with quality of life would perhaps be more informative. This improvement was maintained at 8 weeks overall, the review noted significant heterogeneity of results at 8 weeks at this time point. Collective data on opioid consumption in these studies also showed a significant benefit in the CPN group [41]. A retrospective cohort study by Kambhampati et al. compared outcomes of patients who underwent either percutaneous or EUS-CPN between 2008 and 2015 at Johns Hopkins University School of Medicine. This study suggested a non-statistically significant reduction in procedural complications for EUS-CPN (7% EUS vs. 11% percutaneous, p = 0.51), as well as a non-significant higher immediate response rate in percutaneous CPN (87% versus 72% in EUS-CPN, p = 0.08). Response was defined as a decrease in numeric pain score by ≥3 points. There was no significant difference in quality of life measures, opiate usage, or pain response at 1 month between groups [42].

An interesting study of note by Wyse et al. looked at early EUS-CPN at the time of diagnosis by EUS of unresectable disease [43]. Patients with pain and suspected PC underwent a diagnostic and staging EUS. If diagnosis of unresectable adenocarcinoma was made, patients were randomised to either early EUS-CPN or conventional pain management. The early EUS-CPN group was found to have non-significant improvements in pain response (measured by the Likert scale) and morphine consumption at 3 months compared to standard analgesia (pain response −28.9 [95% CI −67.0 to 2.8], p = 0.09, morphine consumption −49.5 [95% CI −127.5 to 7.0], p = 0.10). Although not statistically significant, these data do suggest that early EUS-CPN at the time of diagnosis could be considered to assist with the often difficult-to-manage analgesic requirements in late-stage PC.

#### **6.2. Biliary duct drainage**

that may include presence of germline mutations may prove to be a more accurate way of identifying HRIs – more research is needed in this area to more-accurately define an at-risk population

The use of EUS in HRIs has been explored in a review by Bhutani et al. [37]. They identified 10 studies utilising screening EUS in families with identified familial PC, PJS, familial atypical multiple mole melanoma syndrome, and several other mutations incurring increased risk. A total of 512 screening EUSs were performed across the 10 studies. The rate of abnormal EUS results (pancreatic duct dilatation or ectasia, observable solid or cystic masses, or parenchymal changes) in this study population was 212/512 (41%). Clinical outcome measures (rate of curative resection for detected cases, overall survival (OS), etc.) were not reported overall. Several studies have demonstrated the ability of EUS in HRI to identify pancreatic dysplasia and IPMN, with no reported false-positives when these cases with abnormal EUS progressed

The largest of these studies was performed in 216 individuals with one of the following risk

• Known familial breast-ovarian cancer patients with at least one first-degree relative af-

Screening was performed on all of these cases with MRI, CT, and EUS. Ninety-two (42%) of participants had an abnormal EUS (at least one pancreatic mass [cystic n = 84, solid n = 3], or pancreatic duct dilatation [n = 5]). Eighty-two of the abnormal EUS cases were IPMNs, and three were neuroendocrine tumours. Five participants went on to have surgical resection, returning three cases of pancreatic dysplasia in <3 cm IPMNs, multiple intraepithelial neoplasms. No cases were identified by CT or MRI that were undetected by EUS. This study lends support to the potential for pancreatic screening in HRIs and supports the choice of EUS as the screening modality over CT and EUS. Further investigation to properly define the characteristics of the at-risk sub-population is needed. The optimal timing and frequency of screening also requires further exploration. The potential merits of screening will need to be balanced against the resource-cost, access,

The first reported use of EUS-guided celiac plexus neurolysis (EUS-CPN) was published by Wiersema in 1996. EUS-CPN was performed on 30 patients with celiac plexus neuropathy; 25 with PC, and 5 with other intraabdominal malignancies. This single-arm study demonstrated efficacy in a mild to moderate reduction in pain scores at 2, 4, 8, and 12 weeks post-procedure (1–10 pain scale 6.1 +/− 3.1 versus 4.8 +/− 2.0, p = 0.004) [40]. Complications were minor and

• Relatives with known familial PC and two affected first-degree relatives (n = 195)

and scalability considerations before routine EUS screening can be supported.

in which a screening population can be shown to be efficacious and cost effective.

to surgical resection [38, 39].

80 Advances in Pancreatic Cancer

• Individuals with PJS (n = 2), or

fected by PC (n = 19).

**6. Therapeutics**

**6.1. Celiac plexus neurolysis**

transient (diarrhoea in four patients).

factors:

EUS-guided biliary duct drainage (EUS-BD) can be performed via several methods, but all involve the direct visualisation via EUS of the pre-obstructed biliary tract and puncture of the pre-obstructive system and confirmation with cholangiography. A guidewire is then inserted and the tract is dilated to create a fistula. These techniques rely on accurate EUS images to target the pancreatic duct, common bile duct, or intrahepatic bile ducts (IHBDs) to create a pancreaticogastrostomy, choledocoduodenostomy, or hepaticogastrostomy, respectively.

EUS-BD can be performed using several techniques:



reducing systemic exposure and toxicity. Encouraging early phase data of several investiga-

Endoscopic Ultrasound in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75211 83

The use of EUS-FNI of ethanol was investigated in 19 patients with unresectable PC by Yang et al. (2009). At follow-up (between 2 and 7 months), a > 70% reduction in size of pancreatic lesions was identified in 12/19 patients (63%), and a 50–70% reduction in size was found in a further 6/19 patients (32%). Seven patients survived beyond 24 months. No major complica-

Levy et al. (2017) performed a prospective study on first-line EUS-FNI with gemcitabine in 36 patients with stage II-IV PCs. Conventional therapies were allowed in all cases at the discretion of the treating Oncologist, but not described in the results. 95 mg (2.5 mL of 38 mg/mL) of gemcitabine was administered via EUS-FNI. OS at 6- and 12-months was 78 and 44%, respectively. Four (20%) patients with stage III disease who underwent EUS-FNI were down-staged

Immunogenic approaches have included EUS-FNI of allogenic mixed lymphocytic culture, immature dendritic cells, tumour necrosis factor alpha (TNF-ɑ), and gene-deleted replication-selective viruses such as ONYX-015. These agents are still under investigation and have been shown to be feasible and safe, however early clinical data has not been overwhelmingly

Brachytherapy induces cell death through the delivery of short-wave beta radiation-emitting particles being placed within the tumour. The local delivery allows for a larger total dose to be delivered to the tumour when compared to external beam radiotherapy (EBRT), with relative sparing of surrounding tissue. Endoscopic brachytherapy (EUS-BT) is being investigated in the management of PC, particularly in locally-advanced unresectable PC, currently treated with either combined chemoradiotherapy with EBRT or palliative chemotherapy alone. Although, the efficacy of EUS-BT has not yet been established, trials in this area including at our institution are ongoing. **Figure 3** below shows the placement of brachytherapy seeds under direction visualisation into an unresectable pancreatic cancer through EUS. **Figure 4** shows a Bremm study taken 1 week after implantation of brachytherapy seeds showing the radiation field created by the implanted seed. **Figures 5** and **6** taken from the same patient shows the radiological response achieved by this technique in this case. More investigation is

Sun et al. utilised EUS-BT in 15 patients with stage III (n = 8), and stage IV (n = 7) pancreatic adenocarcinoma [50]. 27% of cases experienced a partial response, with a mean duration of response of 4.5 months. Rate of disease control was notable at 80% (partial 27%, mild 20%, stable 33%), and 30% of patients showed a clinical benefit (defined by an improvement in Karnofsky Performance Score and pain response to treatment), particularly with regards to pain reduction. Local complications occurred in three patients (pancreatitis and pseudocyst formation), and grade III haematologic toxicity was encountered in three patients without clinical impact [50].

Brachytherapy with several radiation-emitting sources has been trialled (Ra226, Rn222, Au198, Ir192) with significant complications and post-treatment mortality. More recently, I125 has been

tive approaches are emerging, although larger and randomised studies are lacking.

tions were encountered [47].

positive [49].

*7.1.2. Brachytherapy*

and were able to undergo R0 resection [48].

required to optimise patient selection and delivery techniques.

EUS-CDS, EUS-choledochoduodenostomy; EUS-HGS, EUS-hepaticogastrostomy; EUS-RV, EUS-rendezvous.

**Table 1.** Summary of EUS-BD approaches reported in Iwashita et al. [44].

These techniques allow for bypass drainage of bile around the level of obstruction and have been shown to be efficacious with a low rate of serious complications. Iwashita et al. [44] conducted a literature review of EUS-BD and stenting. Results are summarised in **Table 1**.

Complications of EUS-BD were generally limited to peritonitis, pneumoperitoneum, abdominal pain, and perforation. No deaths or need for surgery were reported to have been required for complications arising from EUS-CDS or EUS-HGS. Two deaths were recorded in the 217 cases of EUS-RV; one of these was due to cirrhosis, the other was related to sepsis [44]. No comment on prophylactic antibiotic use was made in this review.

A more recent systematic review by Wang et al. of 1192 patients across 42 studies showed similar success rates, with an overall complication rate of 23.3%. The complications encountered were bleeding (4.0%), bile leakage (4.0%), pneumoperitoneum (3.0%), stent migration (2.7%), cholangitis (2.4%), abdominal pain (1.5%), and peritonitis (1.3%), with no differences in complication rate between transduodenal and transgastric approaches [45]. Grade of complications was not reported. It is important to recognise that EUS-BD has historically been utilised in the setting of failed ERCP for biliary drainage and that this may introduce some selection bias towards more difficult cases, or those who have had recent ERCP, which may be attributable to some of the complications documented in the follow-up period of the studies included in these reviews. A randomised controlled multicentre trial (BILPAL) is currently recruiting to compare EUS-BD with standard ERCP in the first-line setting for palliation of malignant obstructive jaundice [46].

## **7. The future**

#### **7.1. Local administration of anticancer therapies**

The use of EUS as a delivery system for anticancer therapies is an attractive prospect. The poor vascularity and desmoplastic stroma displayed within a malignant pancreatic tumour is likely a significant factor contributing to the relatively poor efficacy of haematogenouslyadministered systemic therapies. EUS may circumvent this limitation by offering locally administered anticancer therapies directly into the tumour.

#### *7.1.1. Intratumoural injections*

EUS-fine needle injection (EUS-FNI) has the potential to improve the delivery of active cytotoxic agents such as chemotherapy or viral therapy to the target cancer more effectively, whilst reducing systemic exposure and toxicity. Encouraging early phase data of several investigative approaches are emerging, although larger and randomised studies are lacking.

The use of EUS-FNI of ethanol was investigated in 19 patients with unresectable PC by Yang et al. (2009). At follow-up (between 2 and 7 months), a > 70% reduction in size of pancreatic lesions was identified in 12/19 patients (63%), and a 50–70% reduction in size was found in a further 6/19 patients (32%). Seven patients survived beyond 24 months. No major complications were encountered [47].

Levy et al. (2017) performed a prospective study on first-line EUS-FNI with gemcitabine in 36 patients with stage II-IV PCs. Conventional therapies were allowed in all cases at the discretion of the treating Oncologist, but not described in the results. 95 mg (2.5 mL of 38 mg/mL) of gemcitabine was administered via EUS-FNI. OS at 6- and 12-months was 78 and 44%, respectively. Four (20%) patients with stage III disease who underwent EUS-FNI were down-staged and were able to undergo R0 resection [48].

Immunogenic approaches have included EUS-FNI of allogenic mixed lymphocytic culture, immature dendritic cells, tumour necrosis factor alpha (TNF-ɑ), and gene-deleted replication-selective viruses such as ONYX-015. These agents are still under investigation and have been shown to be feasible and safe, however early clinical data has not been overwhelmingly positive [49].

### *7.1.2. Brachytherapy*

These techniques allow for bypass drainage of bile around the level of obstruction and have been shown to be efficacious with a low rate of serious complications. Iwashita et al. [44] conducted a literature review of EUS-BD and stenting. Results are summarised in **Table 1**.

EUS-CDS, EUS-choledochoduodenostomy; EUS-HGS, EUS-hepaticogastrostomy; EUS-RV, EUS-rendezvous.

Complications of EUS-BD were generally limited to peritonitis, pneumoperitoneum, abdominal pain, and perforation. No deaths or need for surgery were reported to have been required for complications arising from EUS-CDS or EUS-HGS. Two deaths were recorded in the 217 cases of EUS-RV; one of these was due to cirrhosis, the other was related to sepsis [44]. No

A more recent systematic review by Wang et al. of 1192 patients across 42 studies showed similar success rates, with an overall complication rate of 23.3%. The complications encountered were bleeding (4.0%), bile leakage (4.0%), pneumoperitoneum (3.0%), stent migration (2.7%), cholangitis (2.4%), abdominal pain (1.5%), and peritonitis (1.3%), with no differences in complication rate between transduodenal and transgastric approaches [45]. Grade of complications was not reported. It is important to recognise that EUS-BD has historically been utilised in the setting of failed ERCP for biliary drainage and that this may introduce some selection bias towards more difficult cases, or those who have had recent ERCP, which may be attributable to some of the complications documented in the follow-up period of the studies included in these reviews. A randomised controlled multicentre trial (BILPAL) is currently recruiting to compare EUS-BD with standard ERCP in the first-line setting for palliation of malignant obstructive jaundice [46].

The use of EUS as a delivery system for anticancer therapies is an attractive prospect. The poor vascularity and desmoplastic stroma displayed within a malignant pancreatic tumour is likely a significant factor contributing to the relatively poor efficacy of haematogenouslyadministered systemic therapies. EUS may circumvent this limitation by offering locally

EUS-fine needle injection (EUS-FNI) has the potential to improve the delivery of active cytotoxic agents such as chemotherapy or viral therapy to the target cancer more effectively, whilst

comment on prophylactic antibiotic use was made in this review.

**Table 1.** Summary of EUS-BD approaches reported in Iwashita et al. [44].

**7. The future**

82 Advances in Pancreatic Cancer

*7.1.1. Intratumoural injections*

**7.1. Local administration of anticancer therapies**

administered anticancer therapies directly into the tumour.

Brachytherapy induces cell death through the delivery of short-wave beta radiation-emitting particles being placed within the tumour. The local delivery allows for a larger total dose to be delivered to the tumour when compared to external beam radiotherapy (EBRT), with relative sparing of surrounding tissue. Endoscopic brachytherapy (EUS-BT) is being investigated in the management of PC, particularly in locally-advanced unresectable PC, currently treated with either combined chemoradiotherapy with EBRT or palliative chemotherapy alone. Although, the efficacy of EUS-BT has not yet been established, trials in this area including at our institution are ongoing. **Figure 3** below shows the placement of brachytherapy seeds under direction visualisation into an unresectable pancreatic cancer through EUS. **Figure 4** shows a Bremm study taken 1 week after implantation of brachytherapy seeds showing the radiation field created by the implanted seed. **Figures 5** and **6** taken from the same patient shows the radiological response achieved by this technique in this case. More investigation is required to optimise patient selection and delivery techniques.

Sun et al. utilised EUS-BT in 15 patients with stage III (n = 8), and stage IV (n = 7) pancreatic adenocarcinoma [50]. 27% of cases experienced a partial response, with a mean duration of response of 4.5 months. Rate of disease control was notable at 80% (partial 27%, mild 20%, stable 33%), and 30% of patients showed a clinical benefit (defined by an improvement in Karnofsky Performance Score and pain response to treatment), particularly with regards to pain reduction. Local complications occurred in three patients (pancreatitis and pseudocyst formation), and grade III haematologic toxicity was encountered in three patients without clinical impact [50].

Brachytherapy with several radiation-emitting sources has been trialled (Ra226, Rn222, Au198, Ir192) with significant complications and post-treatment mortality. More recently, I125 has been

**Figure 3.** Brachytherapy seed implantation under direct EUS visualisation.

investigated, with much improved mortality rates, but showed no benefit to cancer-related mortality [51]. Current phase III studies are under way with P32; phase II safety studies have shown a moderate increase rate of serious adverse events per patient when used with 5-fluorouracil (5FU) chemotherapy followed by gemcitabine, compared to EBRT with 5FU chemotherapy, followed by gemcitabine [52]. The varying complication rates reported across studies may also be due to interoperator variability or the low numbers of cases treated. More studies with larger numbers are needed and are currently underway.

was performed and showed an OS for stage III patients of >12 months with an overall median survival time of 9.0 months (95% CI 7.6–10.4 months) [53]. Interestingly, the use of this treatment planning system resulted in no serious adverse events in the study population, which

Endoscopic Ultrasound in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75211 85

Radiofrequency ablation (RFA) induces coagulative necrosis through the application of heat induced by a medium-frequency alternating current [54]. RFA as an anticancer technique is currently utilised in the management of several other malignancies (hepatocellular, renal, etc.), but is also employed in the disruption of aberrant electrical pathways in the heart, as well as in pain medicine, for the ablation of nerve in certain conditions. Until EUS, the utility of external application of RFA has been limited by the sensitivity of pancreatic tissue and

EUS-radiofrequency ablation (EUS-RFA) has been studied in several small case series. There have been two recent systematic reviews published on EUS-RFA in pancreatic malignancies [55, 56]. Rustagi and Chhoda (2017) reported on four clinical studies performed in locally-advanced,

has been a significant criticism of this treatment modality previously.

**Figure 5.** CT and PET scan of pancreatic cancer pre-brachytherapy implantation.

nearby gastrointestinal tissues to RFA, leading to significant complications.

**Figure 6.** CT and PET scan of pancreatic cancer post-brachytherapy.

*7.1.3. Radiofrequency ablation*

There are also some efforts to improve the planning and delivery of brachytherapy to the intended area. Sun et al. (2017) developed a computer-based treatment planning system that was studied in 42 patients with unresectable PC. In this study, EUS-BT using this software

**Figure 4.** Bremm study one week after brachytherapy.

**Figure 5.** CT and PET scan of pancreatic cancer pre-brachytherapy implantation.

was performed and showed an OS for stage III patients of >12 months with an overall median survival time of 9.0 months (95% CI 7.6–10.4 months) [53]. Interestingly, the use of this treatment planning system resulted in no serious adverse events in the study population, which has been a significant criticism of this treatment modality previously.

#### *7.1.3. Radiofrequency ablation*

investigated, with much improved mortality rates, but showed no benefit to cancer-related mortality [51]. Current phase III studies are under way with P32; phase II safety studies have shown a moderate increase rate of serious adverse events per patient when used with 5-fluorouracil (5FU) chemotherapy followed by gemcitabine, compared to EBRT with 5FU chemotherapy, followed by gemcitabine [52]. The varying complication rates reported across studies may also be due to interoperator variability or the low numbers of cases treated. More studies

There are also some efforts to improve the planning and delivery of brachytherapy to the intended area. Sun et al. (2017) developed a computer-based treatment planning system that was studied in 42 patients with unresectable PC. In this study, EUS-BT using this software

with larger numbers are needed and are currently underway.

**Figure 3.** Brachytherapy seed implantation under direct EUS visualisation.

84 Advances in Pancreatic Cancer

**Figure 4.** Bremm study one week after brachytherapy.

Radiofrequency ablation (RFA) induces coagulative necrosis through the application of heat induced by a medium-frequency alternating current [54]. RFA as an anticancer technique is currently utilised in the management of several other malignancies (hepatocellular, renal, etc.), but is also employed in the disruption of aberrant electrical pathways in the heart, as well as in pain medicine, for the ablation of nerve in certain conditions. Until EUS, the utility of external application of RFA has been limited by the sensitivity of pancreatic tissue and nearby gastrointestinal tissues to RFA, leading to significant complications.

EUS-radiofrequency ablation (EUS-RFA) has been studied in several small case series. There have been two recent systematic reviews published on EUS-RFA in pancreatic malignancies [55, 56]. Rustagi and Chhoda (2017) reported on four clinical studies performed in locally-advanced,

**Figure 6.** CT and PET scan of pancreatic cancer post-brachytherapy.

unresectable adenocarcinoma, pNETs, and pancreatic cystic neoplasms (PCNs). The endpoint of most of the reported studies was complication rate, rather than efficacy or survival. The followup period for the articles addressing better-prognosis pancreatic lesions (PCNs / pNETs) was also likely too short to draw conclusions from. Of the 37 cases included across the four studies, adverse events included mild abdominal pain in seven cases, minor duodenal bleeding in one case, jaundice in two cases, duodenal structuring in one case, and cystic fluid collection in one case. The authors concluded that EUS-RFA is feasible and safe in the management of pancreatic lesions, and that more studies are needed with larger sample sizes and longer follow-up periods to investigate EUS-RFA as a treatment modality for PC [56].

from malignant lesions, however due to the fibrotic nature of many of the benign pancreatic lesions (tumour-forming pancreatitis, and benign pancreatitis with fibrosis), specificity is inadequate (67–76%) to replace direct tissue sampling by way of EUS-FNA [60]. Moreover, there are currently several guidelines on the strain ratio cut-off value for differentiation between tissue subtypes, thus harmonisation and standardisation are required between techniques.

Endoscopic Ultrasound in Pancreatic Cancer http://dx.doi.org/10.5772/intechopen.75211 87

Elastography can be measured by either strain elastography by measuring propagated external pressure in the axis of the direction of the applied force, or by shear wave elastography [61]. The latter utilises acoustic radiation force impulses to generate perpendicular 'shear' waves, the velocity of which can be measured in the field of the ultrasound, and are not affected by structures posterior to the target organ in question. Currently, only strain elastography is available via endoscopic approach. Due to the pulsations of the nearby aorta, the future use of shear wave elastography may be advantageous over current strain elastography.

Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) uses intravenously administered hyperechoic microparticles at the time of ultrasound to provide further information regarding the vascularity of the lesion in-question. In the presence of contrast, PC generally appears hypoenhanced and heterogenous, pancreatitis appears isoenhanced, and pNETs cancers appear hyperenhanced [62]. Sensitivity has been reported to be above 90% in multiple studies [63, 64]. However, as some PCs have been reported as being isoenhanced, the specific-

CEH-EUS has been combined with EUS-FNA to improve the accuracy of diagnosis of EUS-FNA. Due to the highly desmoplastic stroma in and around PCs, targeting hypoechoic or isoechoic appearance on CEH-EUS for FNA has been shown to improve diagnostic yield when compared to EUS-FNA alone. Sugimoto et al. (2015) have also shown that CEH-EUS-FNA has the potential to reduce the number of needle passes required for diagnosis [65]. In their conclusion, the authors make the valid point that in all reported cases of needle-tract seeding in EUS-FNA, multiple needle passes were performed. Although in need of validation, CEH-EUS-FNA has the potential to reduce the risk of needle-tract seeding by reducing the required

Confocal laser endomicroscopy (CLE) allows for in vivo histological analysis of tissues in real time. The technique is being developed for the assessment of early pancreatic masses and the surveillance of precancerous lesions. A laser is used to illuminate the target tissue, which is then reflected back through a pinhole to the user. Local or systemic use of fluorescence agents, such as fluorescein can also be used to enhance the image. In endoscopy, CLE can either be done through an integrated endoscope tip, which has been useful for assessing and targeting biopsies of the luminal wall (e.g. oesophagus or stomach), or through needle-based CLE (nCLE), which uses a microfiber that can pass through a 19-gauge needle to assess tissue at

ity of this modality (68%) is also insufficient for replacing EUS-FNA.

**7.4. Contrast-enhanced harmonic ultrasound**

**8. Confocal laser endomicroscopy**

needle passes.

the site of the needle tip.

#### *7.1.4. High-intensity focused ultrasound*

A high-intensity focused ultrasound (HIFU) transducer has been developed for use with endoscopy. HIFU induces cell death by thermogenic coagulative necrosis, similar to RFA, but by emitting ultrasound waves, rather than radiofrequency waves. Tong et al. (2015) have successfully used this probe to induce lesions in normal porcine pancreatic models in vivo [57] to show proof of concept in inducing targeted areas of cell necrosis in pancreatic tissue. HIFU's use in inducing cell death in malignant pancreatic lesions has yet to be elucidated.

#### **7.2. Artificial intelligence**

EUS images can be digitised for analysis by artificial neural networks (ANNs) to quantitatively analyse EUS images as to their likelihood of there being a malignant lesion within them. The use of ANN analysis in pancreatic EUS image analysis was reported by Norton (2016). In a study of 21 patients with PC and 14 patients with focal pancreatitis, ANN analysis was able to differentiate between PC and focal pancreatitis with an accuracy of 89%. This was similar to the endosonographer's impression at time of EUS (accuracy 85%) [58].

Saftoiu et al. performed a similar study among 68 patients; 22 with a normal pancreas, 11 with chronic pancreatitis, 32 with pancreatic adenocarcinoma, and 3 with pancreatic neuroendocrine tumours (pNETs). Reported sensitivity, specificity and accuracy were 91.4, 87.9, and 89.7% respectively and the study concluded that larger, prospective randomised controlled trials were needed to further investigate the use of this adjunct diagnostic tool [59].

With constant improvements in image quality, and further development of ANN models, this may prove a useful adjunct to EUS-based diagnosis, particularly if used by inexperienced endosonographers, and may help to broaden the accessibility of this imaging modality.

#### **7.3. Elastography**

The act of vibrating tissues and measuring the elasticity of their resultant movement is being used in analysis of pancreatic lesions. In general, firmer lesions tend to be malignant; soft lesions are more likely benign. By qualitatively or quantitatively assessing their rebound potential, inferences can be made on the composition of pancreatic lesions.

Due to the differing relative consistency of benign and malignant lesions, quantitative strain elastography results can assist in differentiating subtypes of pancreatic mass. The use of EUS-Elastography has been assessed to have excellent sensitivity (95–99%) for differentiating benign from malignant lesions, however due to the fibrotic nature of many of the benign pancreatic lesions (tumour-forming pancreatitis, and benign pancreatitis with fibrosis), specificity is inadequate (67–76%) to replace direct tissue sampling by way of EUS-FNA [60]. Moreover, there are currently several guidelines on the strain ratio cut-off value for differentiation between tissue subtypes, thus harmonisation and standardisation are required between techniques.

Elastography can be measured by either strain elastography by measuring propagated external pressure in the axis of the direction of the applied force, or by shear wave elastography [61]. The latter utilises acoustic radiation force impulses to generate perpendicular 'shear' waves, the velocity of which can be measured in the field of the ultrasound, and are not affected by structures posterior to the target organ in question. Currently, only strain elastography is available via endoscopic approach. Due to the pulsations of the nearby aorta, the future use of shear wave elastography may be advantageous over current strain elastography.

#### **7.4. Contrast-enhanced harmonic ultrasound**

unresectable adenocarcinoma, pNETs, and pancreatic cystic neoplasms (PCNs). The endpoint of most of the reported studies was complication rate, rather than efficacy or survival. The followup period for the articles addressing better-prognosis pancreatic lesions (PCNs / pNETs) was also likely too short to draw conclusions from. Of the 37 cases included across the four studies, adverse events included mild abdominal pain in seven cases, minor duodenal bleeding in one case, jaundice in two cases, duodenal structuring in one case, and cystic fluid collection in one case. The authors concluded that EUS-RFA is feasible and safe in the management of pancreatic lesions, and that more studies are needed with larger sample sizes and longer follow-up periods

A high-intensity focused ultrasound (HIFU) transducer has been developed for use with endoscopy. HIFU induces cell death by thermogenic coagulative necrosis, similar to RFA, but by emitting ultrasound waves, rather than radiofrequency waves. Tong et al. (2015) have successfully used this probe to induce lesions in normal porcine pancreatic models in vivo [57] to show proof of concept in inducing targeted areas of cell necrosis in pancreatic tissue. HIFU's

EUS images can be digitised for analysis by artificial neural networks (ANNs) to quantitatively analyse EUS images as to their likelihood of there being a malignant lesion within them. The use of ANN analysis in pancreatic EUS image analysis was reported by Norton (2016). In a study of 21 patients with PC and 14 patients with focal pancreatitis, ANN analysis was able to differentiate between PC and focal pancreatitis with an accuracy of 89%. This was similar

Saftoiu et al. performed a similar study among 68 patients; 22 with a normal pancreas, 11 with chronic pancreatitis, 32 with pancreatic adenocarcinoma, and 3 with pancreatic neuroendocrine tumours (pNETs). Reported sensitivity, specificity and accuracy were 91.4, 87.9, and 89.7% respectively and the study concluded that larger, prospective randomised controlled

With constant improvements in image quality, and further development of ANN models, this may prove a useful adjunct to EUS-based diagnosis, particularly if used by inexperienced endosonographers, and may help to broaden the accessibility of this imaging modality.

The act of vibrating tissues and measuring the elasticity of their resultant movement is being used in analysis of pancreatic lesions. In general, firmer lesions tend to be malignant; soft lesions are more likely benign. By qualitatively or quantitatively assessing their rebound

Due to the differing relative consistency of benign and malignant lesions, quantitative strain elastography results can assist in differentiating subtypes of pancreatic mass. The use of EUS-Elastography has been assessed to have excellent sensitivity (95–99%) for differentiating benign

trials were needed to further investigate the use of this adjunct diagnostic tool [59].

potential, inferences can be made on the composition of pancreatic lesions.

use in inducing cell death in malignant pancreatic lesions has yet to be elucidated.

to the endosonographer's impression at time of EUS (accuracy 85%) [58].

to investigate EUS-RFA as a treatment modality for PC [56].

*7.1.4. High-intensity focused ultrasound*

**7.2. Artificial intelligence**

86 Advances in Pancreatic Cancer

**7.3. Elastography**

Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) uses intravenously administered hyperechoic microparticles at the time of ultrasound to provide further information regarding the vascularity of the lesion in-question. In the presence of contrast, PC generally appears hypoenhanced and heterogenous, pancreatitis appears isoenhanced, and pNETs cancers appear hyperenhanced [62]. Sensitivity has been reported to be above 90% in multiple studies [63, 64]. However, as some PCs have been reported as being isoenhanced, the specificity of this modality (68%) is also insufficient for replacing EUS-FNA.

CEH-EUS has been combined with EUS-FNA to improve the accuracy of diagnosis of EUS-FNA. Due to the highly desmoplastic stroma in and around PCs, targeting hypoechoic or isoechoic appearance on CEH-EUS for FNA has been shown to improve diagnostic yield when compared to EUS-FNA alone. Sugimoto et al. (2015) have also shown that CEH-EUS-FNA has the potential to reduce the number of needle passes required for diagnosis [65]. In their conclusion, the authors make the valid point that in all reported cases of needle-tract seeding in EUS-FNA, multiple needle passes were performed. Although in need of validation, CEH-EUS-FNA has the potential to reduce the risk of needle-tract seeding by reducing the required needle passes.
