Introduction

Pancreatic cancer (PC) is one of the most lethal tumors worldwide, and in 2030 it will become the second leading cause of cancer related death (1–3). Computed tomography (CT) and magnetic resonance imaging (MRI) are the gold standards to stage the disease (4). Nevertheless, these imaging modalities are unable to provide real-time information on biological characteristics of tumors, such as vascularity, which is proportional to angiogenesis, growth rate, and necrosis (5,6). Dynamic contrast-enhanced ultrasound (D-CEUS) allows qualitative and quantitative microvascular perfusion assessment in real-time (7).

Aims & Methods

This study aimed to evaluate the role of D-CEUS in the characterization of PC. Thirty-eight patients with suspected PC were prospectively enrolled between October 2022 and March 2023. All patients underwent endoscopic ultrasound guided biopsy for histological diagnosis and CT or MRI for staging. According to these modalities, patients were divided into three categories: resectable PC (R-PC), locally advanced PC (LA-PC), and metastatic PC (M-PC). D-CEUS was performed the same day of lesion biopsy and time-intensity parameters were compared among tumor categories. The diagnostic performances of selected parameters was evaluated by receiver operating characteristic (ROC) analysis.

Results

PC was diagnosed in 36 (94.7%) patients and classified as R-PC, LA-PC and M-PC in 5 (13.9%), 13 (36.1%) and 18 (50%) patients, respectively. Among perfusion parameters, time to peak (TTP) showed a trend to increase in LA-PC patients (median 18.03 sec, interquartile range [IQR] 14) compared to R-PC group (median 12.9 sec, IQR 3.05) (p = 0.05) and it was significantly higher in LA-PC group compared to M-PC group (median 12.35 sec, IQR 4.08) (p = 0.03). A cut-off value < 11.6 sec showed a good accuracy to distinguish LA-PC from M-PC (area under the ROC curve = 0.74) with maximal specificity (100%) but low sensitivity (50%).

Conclusion

Quantitative perfusion parameters extracted from D-CEUS seem to be useful in distinguishing the invasiveness of PC. In particular TTP, a parameter related to blood flow was higher in LA-PC compared to M-PC, suggesting different microvascular characteristics of the tumors. Further studies on larger population are needed to confirm these findings and to explore the biological basis for this phenomenon.

References

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA A Cancer J Clin 2020; 70: 7–30.
2. Rahib L, Smith BD, Aizenberg R, et al. Projecting Cancer Incidence and Deaths to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreas Cancers in the United States. Cancer Res 2014; 74: 2913–2921.
3. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians 2018; 68: 394–424.
4. Ducreux M, Cuhna AS, Caramella C, et al. Cancer of the pancreas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015; 26 Suppl 5: v56-68.
5. Zhang Z, Ji S, Zhang B, et al. Role of angiogenesis in pancreatic cancer biology and therapy. Biomedicine & Pharmacotherapy 2018; 108: 1135–1140.
6. Li S, Xu H-X, Wu C-T, et al. Angiogenesis in pancreatic cancer: current research status and clinical implications. Angiogenesis 2019; 22: 15–36.
7. Dietrich C, Averkiou M, Correas J-M, et al. An EFSUMB Introduction into Dynamic Contrast-Enhanced Ultrasound (DCE-US) for Quantification of Tumour Perfusion. Ultraschall in Med 2012; 33: 344–351.

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 ductal adenocarcinoma (PDAC) is a highly metastatic disease refractory to all targeted and immune therapies. However, our understanding of PDAC microenvironment especially the metastatic microenvironment is very limited partly due to the inaccessibility to metastatic tumor tissues. Here, we aim to carry out the first single-cell transcriptome analysis of PDAC metastatic microenvironment in matched primary tumor and liver metastasis tissues.

Aims & Methods

We collected synchronously resected PDAC primary tumors and matched liver metastases from four PDAC patients and performed single-cell RNA sequencing. We performed comparative analysis on both cellular composition and functional phenotyping between primary and metastatic tumors. We also performed trajectory analysis and cellular interactome analysis in the metastasis microenvironment.

Results

Epithelial cancer cells exhibited distinct transcriptomic profile in liver metastasis with clearly defined evolutionary routes from primary tumor. We identified specific subtypes of stromal and immune cells critical to the formation of the pro-tumor microenvironment in metastatic lesions, including RGS5⁺ cancer-associated fibroblasts, CCL18⁺ lipid-associated macrophages, S100A8⁺ neutrophils and FOXP3⁺ regulatory T cells. We also identified several new biomarkers associated with PDAC metastasis and poor prognosis, such as LITAF, SPRR1B, KLK7 and LGALS9. Cellular interactome analysis further revealed that the lack of tumor-immune cell interaction in metastatic tissues contributes to the formation of the immunosuppressive microenvironment.

Conclusion

Our study provides a comprehensive characterization of the transcriptional landscape of PDAC liver metastasis, which deepens our understanding of the mechanisms underlying the immunosuppressive microenvironment in metastatic PDAC and serves as a valuable resource for the design of novel targeted therapies.

Disclosure

No

Introduction

The retroperitoneal location of the pancreas represents a challenge for the early identification of chronic pancreatitis (CP) and pancreas neoplasms (PN). Imaging and endoscopic ultrasound (EUS) with elastography are helpful resources with variable accuracy. EUS-guided shear wave elastography (EUS-SW) measures tissue elasticity by shear waves inside the organ through acoustic radiation force impulse. Its accuracy has not been assessed for CP and solid PN.

Aims & Methods

We aim to estimate the diagnostic accuracy of EUS-SW for CP and solid PN. Cases with a recently confirmed diagnosis of CP or PN who underwent EUS-SW (12/2020-11/2022) were included. Cases that required EUS for subepithelial lesion assessment comprised a third study group (controls, CG). Age, gender, body mass index (BMI), diabetes, fatty liver disease, alcohol, and tobacco consumption were recorded. An expert endoscopist (RVZ) performed EUS, assessed fatty pancreas score, strain ratio (SR), histogram (SH), and ten measurements of EUS-SW elasticity (SWE) and dispersion (SWD) per case. SWE and SWD variation were based on quotient among interquartile range (IQR) and median. In cases with <30% variation, the association of SWE and SWD was estimated with study groups, baseline and EUS data through multivariate ANOVA regression. SWE and SWD cut-off values were calculated with Youden’s index. Data was analysed in R v4.0.

Results

88 cases were enrolled (37 CG, 14 CP, 37 PN), median age of 62.5 (IQR 53-70), 47.7% female. The proportion of fatty pancreas score II and III was similar in CG (37.8% and 56.8%) and CP (57.1% and 42.9%); there was a significant difference in PN, with a score II, III, and IV of 24.3%, 40.5%, and 29.7%, respectively (p<.001). Median SR was also similar among CG (3.6; IQR 2.9 - 4.3) and CP (3.9; IQR 3.6 - 4.7) but significantly different compared with PN (7.6; IQR 5.3 - 11.1; p<.001). Median SWE and SWD were 10.5 kPa (7.3 - 16.6) and 1.9 [m/s]/kHz (1.6 - 2.4), with a <30% variation in 27 (30.7%) and 57 (64.8%), respectively (table 1). Study groups (CG/CP/PN) and diabetes were associated to a higher SWE and SWD (p<.05). Predicted SWE were significantly different among PN vs CG (-13.1; -24.4 to -1.7; p=.0242) (figure 1). An SWE ≥17.4 diagnosed PN with a sensitivity, specificity, positive and negative predictive values of 75% (19-99), 91% (72-99), 60% (27-99) and 95% (63-99); while an SWD ≥2.31 predicted PN with a diagnostic accuracy of 54% (25-81), 70% (55-83), 35% (21-66), 84% (60-91), respectively.

Conclusion

EUS-SW constitutes an objectively valuable measuring tool for CP and PN diagnostic workups. Larger multicentric diagnostic trials are needed to confirm these findings. NCT05095831.

References

1. Xia C, Yin H, Zhang K, Wang Z, Yang X, Huang H. The global research status and trends of the application of endoscopic ultrasonography in pancreatic tumors over the last decades: A bibliometric study. Front Oncol. 2022 Aug 12;12:980415.
2. Salah NY, Madkour SS, Soliman KS. Pancreatic shear wave elastography in children with type 1 diabetes: relation to diabetes duration, glycemic indices, fasting C-peptide and diabetic complications. Pediatr Radiol. 2022 Nov;52(12):2348-2358. doi: 10.1007/s00247-022-05363-1. Epub 2022 Apr 23.
3. Fujita Y, Kitago M, Abe T, et al. Evaluation of pancreatic fibrosis with acoustic radiation force impulse imaging and automated quantification of pancreatic tissue components. Pancreas. 2018;47:1277–1282.
4. Jesper D, Fiedler S, Klett D, Waldner MJ, Schellhaas B, Zundler S, Neurath MF, Pfeifer L. Shear Wave Dispersion Imaging for the Characterization of Focal Liver Lesions - A Pilot study. Ultraschall Med. 2022 Oct;43(5):507-513.
5. Korta Martiartu N, Nambiar S, Nascimento Kirchner I, Paverd C, Cester D, Frauenfelder T, Ruby L, Rominger MB. Sources of Variability in Shear Wave Speed and Dispersion Quantification with Ultrasound Elastography: A Phantom Study. Ultrasound Med Biol. 2021 Dec;47(12):3529-3542.

Disclosure

Carlos Robles-Medranda is a key opinion leader and consultant for Pentax Medical, Boston Scientific, Steris, Medtronic, Motus, Micro-tech, G-Tech Medical Supply, CREO Medical, EndoSound, and Mdconsgroup. The other authors declare no conflicts of interest.

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

The benefits of neoadjuvant therapy for patients with pancreatic cancer (PC) with portal venous involvement are still a matter of debate. The aim of this study is to compare the short- and long-term outcomes of surgery with or without neoadjuvant therapy (NAT) in patients with PC with suspicion of venous involvement.

Aims & Methods

A multicenter retrospective cohort study was conducted to compare patients who underwent upfront surgery (US) vs patients who underwent surgery after NAT for PC with suspicion of venous involvement between 2007 and 2017. The primary endpoints were short-term morbidity and mortality, overall survival and disease-free survival.

Results

We included 690 patients who underwent US and 361 patients with NAT from 9 centers. Patients with NAT had more suspicion of radiological SMV-PV involvement(83.6% vs 96.9%, p<0.001), but received fewer SMV-PV resections (79.3% vs 53.7%, p<0.001) and in the final pathology had less SMV-PV infiltration (65.9% vs 52.3%, p<0.001), perineural invasion (90.1% vs 75.2%, p<0.001), angioinvasion (76.7% vs 59.9%, p<0.001), lymph node involvement (83.6% vs 60.6%, p<0.001) and R1 resections (67.2% vs 44.7%, p<0.001). In patients undergoing venous resection, there were no differences between the US and NAT patients in major postoperative complications (20.0% vs 22.8%, p<0.50) and reoperations (10.2% vs 11.4%, p<0,66). When venous resection was not performed, patients with NAT had significantly fewer (Clavien-Dindo ≥IIIb) postoperative complications (24.4% vs 10.8%, p=0.02), fewer reoperations (11.2% vs 3.0%, p=0.006), and less 90-day mortality (7.7% vs 2.4%, p=0.03). Furthermore, patients with NAT had a significantly better survival of 27.3 compared to 21.2 months in patients with US (p = 0.003).

Table 3. Short-term morbidity and mortality

Conclusion

NAT should be considered in patients with PC with venous involvement, since it might allow a better selection of patients and is associated with less degree of major postoperative complications and better overall survival.

Introduction

Diabetes mellitus (DM) is an independent risk factor for colorectal cancer (CRC). Glycemic control and variability are the main components of glycemic homeostasis. We aim to identify the association of glycemic control and variability with CRC development in individuals with DM.

Aims & Methods

Patients with DM diagnosed between 2005 and 2013 were followed up till 2020 (CRC or death occurrence) via a territory-wide electronic healthcare registry from Asia. We excluded age <18 years, those with human immunodeficiency virus, inflammatory bowel disease, insufficient HbA1c measurements, and prior diagnosed CRC. We identified DM following the American Diabetes Association criteria with at least two abnormal tests of hemoglobin A1c (HbA1c) ≥6.5% or fasting plasma glucose ≥7 mmol/L; antidiabetic medication use; or International Classification of Diseases Ninth Revision (ICD-9). An initial three-year lead-in period from the DM diagnosis date was applied to evaluate glycemic control and variability: optimal glycemic control was regarded as mean HbA1c <7% from at least two measurements; lower glycemic variability was regarded as measurements of <25% quantile, including standard deviation (SD), coefficient of variation, and average successive variability. Cox regression models with inverse probability of treatment weighting (IPTW) of study characteristics were used to calculate hazard ratios (HRs) of CRC with optimal glycemic control.

Results

During a median follow-up of 6.7 (interquartile: 5.3-8.7) years, 2,231 (1.3%) of 171,270 patients with DM (mean [SD] age: 61.7 [11.7] years; male: 90,441 [52.8%]) developed CRC. Patient characteristics were well balanced after IPTW (all standardized mean differences <0.01). The 12-year cumulative incidence of CRC was 2.2% (95%CI 2.0%-2.4%) and 2.7% (95%CI 2.5%-3.0%) in optimal and suboptimal glycemic control respectively with an HR of 0.83 (95%CI 0.76-0.90). The association was validated in sensitivity analyses (HRs: 0.79-0.88) and consistent across subgroups regardless of at-risk age (40-75 years), obesity, smoking status, aspirin use, and diabetes-related comorbidity (HRs: 0.73-0.86). CRC risk increased incrementally with HbA1c increases beyond ≥7% in the multivariate Cox regression model, from an adjusted HR of 1.31 (95%CI 1.17-1.48) for HbA1c 7.0%-7.5%, to 1.36 (95%CI, 1.16-1.59) for HbA1c 7.5%-<8.0%, to 1.47 (95%CI, 1.20-1.80) for HbA1c 8.0%-<8.5%. The beneficial effects of glycemic control were limited to the left colon (HR 0.82, 95%CI 0.71-0.94) and rectum (HR 0.81, 95%CI 0.68-0.96) but not to the right colon (HR 0.92, 95%CI 0.75-1.11). Among those who had colonoscopy during the study period (n=14,399), optimal glycemic control was associated with lower CRC risk in patients with (HR 0.78, 95%CI 0.67-0.92) and without (HR 0.85, 95%CI 0.73-0.98) adenomas. Lower vs. higher glycemic variability yielded consistent associations for CRC risk (HRs: 0.81-0.85; All P <0.001). Optimal glycemic control had no association with adenoma (HR 1.01, 95%CI, 0.96-1.07) and advanced adenoma (HR 0.98, 95%CI 0.87-1.10) development.

Conclusion

Optimal glycemic control was independently associated with reduced CRC development in patients with DM, while the worsening of glycemic control was associated with an incrementally increased cancer risk. Our study findings can aid CRC risk stratification of among patients with DM.