Introduction

Single-molecule fluorescence microscopy has been researched for diagnosis of disease and detecting drugs or substances at the molecular level. It is known to detect the target proteins more precisely than ELISA and has a higher multiple detection rate, with small sample volume and at low cost. Pancreatic cancer often presents at an advanced stage. So there is a demand for early detection.

Aims & Methods

The aim of this pilot study is to check the feasibility of this technique to diagnose the pancreatic cancer. From April 2016 to June 2021, 16 pancreatic cancer patients and 21 non-pancreatic cancer patients were enrolled in the study at Seoul National University of Bundang Hospital. 15 markers (CA19-9, CRP, CA-125, D-dimer, Lumican, Cathepsin-D, IL-6, LRG-1, IFN-r, Beta-2, CEA, Clusterin, TTR, IL-4, and C5a) were detected from blood sample using single-molecule fluorescence microscopy. To create a train and test set for our research, we split the enrolled patients into halves. The primary outcome of the study is the accuracy, which is defined as the number of correct predictions, where patients are predicted as patients and controls are predicted as controls, divided by the total count. We analyzed the classification accuracy of each group and examined the accuracy based on the combination and number of markers used. Although the sizes of the training set and the testing set were equal, we randomly split each sample into either the training or testing set, and repeated this process 1,000 times.

Results

Eight out of 16 pancreatic cancer patients were used for training and the remaining 8 for testing. For the non-pancreatic cancer patients, 11 of the 21 blood samples were used for training, and the other 10 for testing.
In the classification accuracy of diagnosis, we tested the accuracy by utilizing Gaussian Naïve Bayes and Support Vector Machine. In case of Gaussian Naive Bayes for the train set, the average accuracy was 99.2%, the standard deviation was 0.019. When applied to the test set, the accuracy was 86.3%, with a standard deviation of 0.074. In case of Support Vector Machine for the train set, the average accuracy was 75.6%, the standard deviation was 0.004. When tested on the test set, the accuracy was 77.6% with a standard deviation of 0.076.
For the accuracy according to the number of biomarkers used, the accuracy was calculated by adding one biomarker at a time in the order previously listed. Accuracy tended to increase as markers were added, the highest accuracy was achieved when using 10 biomarkers (88.4%), and adding more biomarkers from the 11th to 15th actually decreased the accuracy (lowest 85.5% to highest 87.8%).

Conclusion

In this pilot study, we identified that single molecule counting technology showed a feasibility for the new technique to differentiate the patients with pancreatic cancer from healthy control. Further studies with more samples and appropriate selection of biomarkers, and optimization of classification model are necessary to fit the best performance of this novel technique. Utilizing this novel technique with multiple biomarkers in combination is expect to enable low-cost, small-sample volume, and high- accuracy diagnosis in pancreatic cancer.

Introduction

Pancreatic cancer (PC) is one of the fatal malignant tumors, with a 5-year survival rate is approximately 6%, and is expected to become the second leading cause of cancer deaths by 2030. The poor prognosis of PC is associated with the tumour microenvironment, characterized by excessive fibrosis and extracellular matrix deposition, known as desmoplasia. PC’s highly desmoplastic property not only increases the malignancy of the tumor but also inhibits the penetration and diffusion of anti-cancer drugs, related to drug resistance. Chauhan et al. demonstrated that the angiotensin inhibitor (ASI), losartan reduced stromal collagen and hyaluronan production, thus improving the efficacy of chemotherapy in PC models. Several retrospective studies have reported that the ASI usage group showed higher overall survival (OS) and progression-free survival compared to the non-ASI usage group in PC patients. However, most of the previous studies on ASI in PC patients were based on retrospective data from single institutions. Recently, real-world big data study could explain this subject.

Aims & Methods

In this study, we aimed to conduct whether ASI use in PC patients improve OS using National Health Information Database of the National Health Insurance Service, which represents the entire Korean population. We assessed 209,723 participants for eligibility, diagnosed with pancreatic cancer between 2002 and 2020. A total of 64,219 PC patients were enrolled and divided into 3 groups [chronic ASI users with hypertension (HTN), n=13,239; non-ASI users with HTN, n=5,963; non-HTN group, n=45,017]. We performed propensity score matching to balance the baseline characteristics of the 3 groups and to reduce potential confounders using a logistic regression model with adjustment for the following: age; sex; region of residence (urban or rural); household income; underlying disease of HTN, diabetes mellitus, cardiovascular disease, cerebrovascular disease, chronic kidney disease or chronic pancreatitis; Charlson Comorbidity Index (0, 1 or ≥2); concurrent use of aspirin, metformin, statin; PC surgery type; radiotherapy; and chemotherapy.

Results

Multivariate analysis using Cox regression analysis for matched cohort presented ASI usage, female, younger, history of chronic pancreatitis, CCI ≥2, concurrent use of statin, and receiving distal pancreatectomy were significantly associated with longer OS. In addition, Kaplan-Meier curve for OS of 3 groups according to ASI usage showed that chronic ASI users presented significantly longer OS than non-ASI users and non-HTN group [Hazard ratio, chronic ASI users (control) versus non-ASI users 1.447; chronic ASI users (control) versus non-HTN group 1.518; P value < 0.001].

Conclusion

We found that the use of ASI after PC diagnosis is associated with longer survival in PC patients. Additional well-designed randomized controlled studies are needed to confirm these findings in the future.

References

1. Rahib, L., B. D. Smith, R. Aizenberg, A. B. Rosenzweig, J. M. Fleshman and L. M. Matrisian (2014). "Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States" Cancer Res 74(11): 2913-2921.
2. Encarnación-Rosado, J. and A. C. Kimmelman (2021). "Harnessing metabolic dependencies in pancreatic cancers." Nature Reviews Gastroenterology & Hepatology 18(7): 482-492.
3. Thomas, D. and P. Radhakrishnan (2019). "Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis." Molecular cancer 18: 1-15.
4. Chauhan, V. P., J. D. Martin, H. Liu, D. A. Lacorre, S. R. Jain, S. V. Kozin, T. Stylianopoulos, A. S. Mousa, X. Han, P. Adstamongkonkul, Z. Popović, P. Huang, M. G. Bawendi, Y. Boucher and R. K. Jain (2013). "Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels." Nat Commun 4: 2516.
5. Pinter, M. and R. K. Jain (2017). "Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy." Sci Transl Med 9(410).

Introduction

Pancreatic cancer (PC) is characterized by an exceptionally aggressive biology and high tumor heterogeneity causing considerable variations in therapy response. Patient-derived organoids (PDOs) reflect parental tumor features and represent a powerful preclinical tool to predict drug response and harness personalized treatment. In clinical practice, PDO-guided selection of effective drugs may provide substantial benefit and improve outcomes.

Aims & Methods

We have derived >40 PDOs from treatment-naïve and pretreated PC patient primary tumor and metastases (after ultrasound-guided biopsy, endoscopic ultrasound-guided biopsy or surgical resection) with a reliable efficacy. PDO drug response was evaluated using a cytotoxicity assay. Using Jenks natural breaks classification method, we clustered response (AUC) for each drug and correlated it to patient response.

Results

The implementation of an automated pipetting system and the subsequent miniaturization of drug screenings significantly enhanced our process capacity, conferring the possibility to extend our panel to a second list of approved targeted substances and further reducing the time before pharmacotyping. The validity of our approach was assessed via re-pharmacotyping a set of PDOs. Following up our feasibility trial (Beutel, 2021), we validated the accuracy of our model on a greater number of PC patients. Our model allowed overall a successful drug-response prediction in naïve patients with an accuracy of 85.7% for both first and second-line regimens. Prediction power remained lower for pretreated patients, with a precision of 57.1% for subsequent lines. A trend was also observed towards a better performance of the system in prognosticating chemoresponsiveness vs unresponsiveness (89.5% vs 68.8%). Finally, the administration of a regimen predicted to be efficient translated into a significantly longer progression-free survival. The access to longitudinal biopsies allowed us to conduct whole exome sequencing on 14 PDOs to capture a comprehensive genetic profiling over the time of treatment, notably revealing a CHEK2-mutated patient who responded over time upon PARP inhibitor maintenance therapy, in line with our PDO-based response prediction, further highlighting the robustness of our method and algorithm.

Conclusion

Overall, we report a robust and clinically-relevant preclinical tool for drug response prediction, paving the way towards an PDO-based true precision medicine in clinical routine.

Introduction

Pancreatic cancer (PC) accounts for 0.5 million new cases and 4.7% of the world's cancer-related deaths in 2020^1,2. Endoscopic ultrasound (EUS) guided Fine Needle Biopsies (FNB) are the current standard of care for confirming suspicious lesions, however the diagnostic accuracy is reported below 70%^3-5. Rapid on-site evaluation (ROSE) improves the diagnostic performances of biopsies via an on-site pathological assessment to reduce the number of needle passes, complication rates, and the need for additional procedures⁶. However, availability of an on-site pathologist is often not feasible. NovaScan has pioneered the use of an impedance spectroscopy biomarker for cancer detection in different tissues based on the Cole Relaxation Frequency (CRF). NovaScan has developed a ”smart ROSE” device that assesses PC presence in FNBs obtained during endoscopic procedures ex vivo, in real-time and on-site, without altering the tissue sample or affecting the workflow.

Aims & Methods

Data were collected in a double-blind, IRB approved study from a cohort of 21 patients (9 males, 12 females) undergoing EUS procedures for suspected pancreatic lesions at the Texas International Endoscopy Center. FNBs were performed with a 22 gauge biopsy from a transduodenal approach. Each biopsy sample was transferred onto a disposable strainer allowing for any excess fluid to drain. An electrode for scanning was placed onto the core samples for data collection with the "smart ROSE," a low cost, portable device that can be used in the operating room. The device measures impedance spectroscopy in the 1 kHz - 10 MHz frequency range and derives a bio impedance biomarker via custom-designed hardware. The assessment of the sample is completed in a few seconds and subsequently, the sample is flushed into a pathology jar to undergo the standard workflow for cytology. The algorithm for extracting the bioimpedance biomarker from the measurement was developed based on our previous preclinical study with transgenic (KPC) mice⁷; pancreas samples with a CRF biomarker below 1 MHz were considered noncancerous, while biomarker values above 1MHz or the absence of a biomarker reading were considered cancerous.

Results

PC assessment provided by nsCanary was validated against pathology outcomes for each biopsy sample. Findings showing a sensitivity of 80% and a specificity of 87.5% are reported in Table 1.

Conclusion

We believe the "smart ROSE" device will provide immediate feedback to the endoscopist on cancer presence and on sample adequacy. This device is intended to support the decision-making process by enabling clinicians to overcome the challenge of proving cancer presence during the first biopsy procedure, ultimately avoiding revisits and unnecessary trauma.

References

1. S. Kato and K. Honda. Use of biomarkers and imaging for early detection of pancreatic cancer. Cancers, 12(7):1965, 2020.
2. M. R. Young, N. Abrams, S. Ghosh, J. A. S. Rinaudo, G. Marquez, and S. Srivastava. Prediagnostic image data, artificial intelligence, and pancreatic cancer: a tell-tale sign to early detection. Pancreas, 49(7):882–886,2020.
3. S. Varadarajulu and M. B. Wallace. Applications of endoscopic ultrasonography in pancreatic cancer. Cancer Control, 11(1):15–22, 2004.
4. P. Michl et al. UEG position paper on pancreatic cancer. Bringing pancreatic cancer to the 21st century: Prevent, detect,and treat the disease earlier and better. UEG journal, 9(7):860–871, 2021
5. D. T. de Moura et al. Evaluation of endoscopic ultrasound fine-needle aspiration versus fine-needle biopsy and impact of rapid on-site evaluation for pancreatic masses. Endoscopy International Open, 8(06):E738–E747, 2020.
6. J. B. Klapman, R. Logrono, C. E. Dye, and I. Waxman. Clinical impact of on-site cytopathology interpretation on endoscopic ultrasound-guided fine needle aspiration. The American journal of gastroenterology, 98(6):1289–1294, 2003.
7. Bogdanowicz, Les, et al. Cole Relaxation Frequency: A Parameter for Pancreatic Cancer Detection. The American Journal of Gastroenterology 117(10S):p e24-e25, October 2022

Introduction

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is a precursor of pancreatic cancer. While earlier research has shown a high prevalence of synchronous/metachronous extrapancreatic tumors in IPMN patients, these studies have often been small with retrospective data collection.

Aims & Methods

Through the Epidemiology Strengthened by histoPathology Reports in Sweden (ESPRESSO) cohort, consisting of computerized histopathology data from all 28 pathology departments in Sweden during the period 1965-2017, we retrieved data on IPMN.
Each index case was matched to ≤5 general population controls.
Through Cox proportional hazards regression models, we estimated hazard ratios (HRs) for future gastrointestinal (GI) cancer precursors and death. In secondary analyses, full siblings were used as comparators.
We excluded IPMN patients with high-grade dysplasia (HGD) to avoid the risk of misclassification.
Outcome topography included esophagus, stomach, colon and rectum and outcome morphology included Barrett’s esophagus, gastric metaplasia, mucosa type 1-3, tubulous adenoma, sessile serrated polyp, tubulovillous adenoma and villous adenoma.

Results

A total of 117 patients with IPMN, 539 age- and sex-matched controls, and 122 siblings were included. Among patients with IPMN, the mean age at diagnosis was 68.3 years and 48% were female.
Compared to IPMN patients, sibling controls were slightly younger (mean 65.5 years).
Patients with IPMN were also more likely to have prior diabetes, chronic obstructive pulmonary disease, obesity, dyslipidemia, and alcohol-related disease.
Almost all IPMN cases (97%) had ≥3 healthcare visits within the last year before diagnosis.
A Charlson Comorbidity Index score of ≥3 was seen in 28% of IPMN cases, compared to in 11% of controls and 9% of siblings.
IPMN cases were at increased risk of earlier GI cancer precursors compared to controls from the general population (OR=6.67; 95%CI=3.45-14.29), but the association failed to reach statistical significance when we compared with siblings (OR=2.00; 95%CI=0.92-4.35).
Over a median of 2.1 years of follow up, we confirmed two (1.7%) incident GI cancer precursors in IPMN vs. four (0.7%) in controls, corresponding to an HR of 1.89 (95%CI=0.34-10.55).
By contrast, IPMN patients were at increased risk of death (HR 3.61 (95%CI=1.79-7.27)).
The most common cause of death in IPMN was pancreatic cancer (n=14; 45.2% of all deaths).
Pancreatic cancer was the cause of death in only two (2.7%) controls and one (7.7%) sibling.
Extrapancreatic cancers were found in eight (6.8%) IPMN patients, 21 (3.9%) controls and four (3.3%) siblings.

Conclusion

We found no association between IPMN and other GI cancer precursors. This argues against comprehensive routine surveillance for other GI cancer precursors in IPMN patients.
Mortality was increased in IPMN with pancreatic cancer being the most common cause of death, indicating the need for lifelong follow up in all resected and non-resected patients with IPMN.

Disclosure

Dr Ludvigsson is coordinating a study on behalf of the Swedish IBD quality register (SWIBREG). This study has received funding from the Janssen corporation. Dr Ludvigsson has also received financial support from MSD to develop a paper reviewing national healthcare registers in China. Dr Vujasinovic and Dr Löhr have received lecture fees from Abbott and Viatris. Dr Vujasinovic and Dr Löhr have also received financial support for writing a scientific book from Viatris. All other authors declare that they have no conflicts of interest and nothing to declare.

Introduction

Metastatic pancreatic adenocarcinoma (mPDAC) has poor prognosis with a 5-year survival rate of 3%. In non-metastatic, unresectable locally advanced pancreatic cancer (LAPC) patients, endoscopic-ultrasound (EUS)-guided intra-tumoral ³²P-microparticles implantation resulted in 90.5% local disease control rate [LDCR], defined as Stable Disease [SD] or better, at 16 weeks¹. This is the first study to examine the outcome of ³²P-microparticles (OncoSil™; OncoSil Medical) implantation, in combination with chemotherapy, for treatment of patients with mPDAC.

Aims & Methods

Outcome data of mPDAC patients treated with combination of chemotherapy and intra-tumoral ³²P microparticles (8% of tumour volume, delivering ~100Gy to the tumour) from 5 centres in Australia and UK were retrospectively reviewed. In all cases, ³²P implantation was performed after at least 2 cycles of chemotherapy, which were either FOLFIRINOX or gemcitabine/nab-paclitaxel (Gen-Nab). Data were expressed as median value and P<0.05 was considered as significant.

Results

14 patients (7F:7M; age: 64.5 years; ECOG 0/1/2: 21.4%/57.1%/21.4%) were treated with Gem-Nab (n=10) and FOLFIRINOX (n=4) prior to ³²P-microparticles implantation. Patients had a median of 3 metastases (range, 1-7) in liver (42.9%), lung (35.7%), liver/lung (7.1%), liver/peritoneum (7.1%) or lung/peritoneum (7.1%), with median primary tumour longest diameter [LD] and volume of 40.5mm and 21.8cm³, respectively. ³²P microparticles were implanted with a 100% technical success, at a median 3.1 months from the initial chemotherapy. Prior to OncoSil^TM implantation, only 50% (n=7) had evidence of either stable disease (n=5) or partial response (n=2) based on RECIST criteria. After OncoSil^TM implantation, local disease control rate was 100% at 3 months (stable disease:10 patients; partial response: 4 patients). There was a median 25% reduction in primary tumour LD, with 1 (7%) patient having a marked response and underwent resection (R0 on histology). Median CA19-9 declined from 856.5U/mL to 72U/mL. After a median follow-up of 35.3 months, site of progression after Oncosil implantation were: distant (n=8), local/distant (n=4), local (n=1) and no progression (n=1). Median progression-free survival (PFS) after ³²P implantation was 5.6 months (95% CI: 4.3-non-calculable [nc]), and the overall median survival was 13.9 months (95% CI: 12.2-nc). No Grade 4/5 acute toxicities were observed; 3 (21.4%) patients had device- or procedure-related Grade 1/2 AEs (abdominal pain; nausea; fatigue; dyspepsia) that were also attributed to chemotherapy.

Conclusion

The addition of EUS-guided ³²P-microparticles implantation to standard chemotherapy is feasible and safe for mPDAC patients, with 100% local disease control rate at 3 months post-implantation. This promising data suggests the role of combined intra-tumoral ³²P-microparticles and chemotherapy in the treatment of mPDAC and warrants further evaluation in a large prospective trial.

References

1. Ross, P.J., et al., PanCO: An open-label, single-arm pilot study of phosphorus-32 (P-32; Oncosil) microparticles in patients with unresectable locally advanced pancreatic adenocarcinoma (LAPC) in combination with FOLFIRINOX or gemcitabine + nab-paclitaxel (GNP) chemotherapies. Journal of Clinical Oncology, 2019. 37(15_suppl): p. 4125-4125.

Disclosure

Authors include 2 members of OncoSil Medical whom have assisted in obtaining data from multiple centres however first author collated and analysed data.