Introduction

The complex biology of pancreatic ductal adenocarcinoma (PDAC) remains a significant challenge and limits overcoming its dismal prognosis. The tumor microenvironment (TME), shaped by dynamic interactions between cancer-associated fibroblasts (CAFs), immune and tumor cells, plays a crucial role in PDAC pathogenesis. Our investigation into homologous recombination deficiency (HRD), caused by mutations in genes like ATM, revealed its role in promoting PDAC aggressiveness and triggering a pronounced desmoplastic reaction, suggesting a unique TME programing. We have shown that the loss of ATM in the neoplastic epithelium reprograms CAFs through the TGFβ signaling to promote cancer aggressiveness. Additionally, preliminary data revealed distinct immune profiles in ATM-deficient and proficient tumors.

Aims & Methods

To capture the immune profiles of ATM-deficient PDACs, and decipher specific oncogenic tumor–stroma interactions, we first conducted single cell-resolved multiomics analyses of murine ATM and/or P53-depleted PDACs. Histopathological analyses and validation using publicly available human datasets were performed to further characterize ATM loss-specific immune patterns in pancreatic cancer.

Results

Mouse tumor analyses, using single-nucleus multiomics RNA/ATAC sequencing and multiplex immunostainings, revealed alterations in immune cell contents, e.g. reduced macrophage populations and reduced M2 polarization in ATM-deficient tumors. ATM loss-specific immune molecular signatures were further investigated and correlated with human PDAC RNA sequencing data (TCGA, PanCancer Atlas). Molecular signatures and cell-cell communication inference revealed ATM-specific tumor–TME interactions and identified the TGFβ signaling as a core driver of the interplay between CAFs, immune cells, and a particularly aggressive EMT-like tumor cell subpopulation overrepresented in ATM-depleted tumors. Strikingly, we also observed distinct communication patterns between CAFs and immune cells. Finally, a combinatorial therapy targeting the TGFβ-driven tumor–stroma dialog reversed the cancer-promoting TME remodeling and exacerbated the therapeutic response to FOLFIRINOX in vivo, exclusively in ATM-deficient HRD PDACs.

Conclusion

Through single cell-resolved multiomics analyses of ATM-deficient PDACs, and validation in human cases, we unveil transcriptional, translational, and secretory regulatory events, shed light on the intricate interplay between tumor genetics and PDAC microenvironment, and pave the way for the elaboration of novel personalized therapies.

Introduction

It is unknown how stent types relate to clinical outcomes of endoscopic ultrasound (EUS)-guided drainage of pancreatic pseudocysts. This multicenter retrospective study aimed to compare the clinical outcomes between a lumen-apposing metal stent (LAMS) and a plastic stent.

Aims & Methods

Among 357 patients with pancreatic fluid collections in a large multi-institutional WONDERFUL consortium, we included 123 patients who received EUS-guided drainage of a pancreatic pseudocyst (16 and 107 cases with LAMS and plastic stent(s), respectively). We examined clinical treatment success, procedure-related adverse events, and pseudocyst recurrence.

Results

There were no differences between the groups regarding demographics (e.g., age and sex) and disease characteristics (e.g., size, encapsulation status, and the timing of drainage in relation to the onset of acute pancreatitis). The clinical success rates were comparable between the LAMS and plastic stent groups (94% vs. 87%, respectively; P = 0.40). The stent types were not associated with the time to clinical success (median, 25 days vs. 22 days for the LAMS and plastic stent groups, respectively; P = 0.56), the overall rate of procedure-related adverse events (0% vs. 5.6%, P = 0.33), or the rate of recurrence following clinical success (6.7% vs. 17%, P = 0.19).

Conclusion

In patients receiving EUS-guided drainage of pancreatic pseudocysts, clinical outcomes appeared to be comparable between the LAMS and plastic stent groups. If validated, our findings would support the feasibility of plastic stents in this patient population, which is a more cost-effective treatment modality than LAMSs. We, the WONDERFUL study group, have launched a randomized non-inferiority trial of plastic stents compared to a LAMS in this setting (NCT#06133023).

Disclosure

H.I. declares research funding from Boston Scientific Japan, Fujifilm, and Piolax Medical Devices; and honoraria from Boston Scientific Japan, Century Medical, Create Medic, Fujifilm, Gadelius Medical, Hitachi Medical, Japan Lifeline, Kaneka, Kawasumi Laboratories, Olympus Medical, Piolax Medical Devices, Sumitomo Bakelite, UMIDAS, and Zeon Medical; and contributions from Boston Scientific Japan, Gadelius Medical, Japan Lifeline, and Zeon Medical. Y.N. is an editorial board member of Digestive Endoscopy and declares research funding from Boston Scientific Japan, Century Medical, Fujifilm, Gadelius Medical, HOYA Pentax Medical, Hitachi Medical, Kaneka, and Medico’s Hirata; and honoraria from Boston Scientific Japan, Fujifilm, Gadelius Medical, Hitachi Medical, J-MIT, Medico’s Hirata, and Olympus Medical. This work was not supported by any of those companies. The other authors declare no conflicts of interest related to this article.

Introduction

The combination of standard chemotherapy and phophorus-32 (³²P) microparticle intra-tumoural implantation has revealed encouraging results for patients with locally advanced pancreatic cancer (LAPC). As no direct comparison has been made, our aim was to compare FOLFIRINOX alone and FOLFIRINOX with ³²P implantation in a propensity-score weighted analysis.

Aims & Methods

We conducted a retrospective cohort study comparing LAPC patients with combination chemotherapy and ³²P implantation at 2 centres with patients with chemotherapy only (discussed at hepatobiliary multidisciplinary team meetings or underwent diagnostic endoscopic ultrasound for pancreatic cancer) from a single centre, from August 2017 to January 2023. Landmark analysis was used to overcome immortal time bias. Propensity score weighting was further performed to minimise baseline confounders. Primary outcome was overall survival.

Results

104 patients were considered. The landmark date was designated as 3 months after initiation of chemotherapy. After excluding patients who died before the landmark, 101 patients were included in the propensity-score weighted analysis (35 with ³²P implantation and chemotherapy, 66 with chemotherapy only). The restricted mean survival time (RMST) within 24 months after initiation of chemotherapy was estimated to be 112 days longer for patients with ³²P implantation and chemotherapy (459 days, 95%CI 393-536) compared to patients with chemotherapy only (347 days, 95% CI 308-392). The restricted mean local progression free time within 24 months after initiation of chemotherapy is estimated to be 112 days (95% CI 36-187) longer for patients with ³²P implantation and chemotherapy compared to patients with chemotherapy only. Average tumour size at 6 months was 12.8mm smaller (95% CI 4.69-20.9, p=0.002) with combination therapy than with chemotherapy only. The probability of downstaging if all patients were to be treated with combination therapy was 22.3% higher (95% CI 5.12%, 39.5%, p=0.03) than the probability with chemotherapy only.

Conclusion

This first comparative study between standard chemotherapy and chemotherapy with additional ³²P microparticles implantation has demonstrated significant survival, disease control and downstaging benefits of combination therapy with chemotherapy and ³²P microparticle implantation.

Disclosure

Nil

Introduction

Hormonal exposure influences cancer initiation and progression in several organs, including the pancreas. The association between gynecological factors and the onset of pancreatic adenocarcinoma (PDAC) is conflicting, with some studies showing a reduced risk of PDAC with the use of hormonal replacement therapy (HRT) or with having had a late-onset menopause. Nonetheless, the association between gynecological factors and disease prognosis has not yet been investigated. Our objective was to evaluate whether gynecological/reproductive factors affect PDAC prognosis.

Aims & Methods

This was a single-center retrospective analysis of a prospectively maintained database of PDAC patients. Risk factors were assessed via questionnaires regarding gynecologic/reproductive factors (age at menarche, menopause, years of fertility, breastfeeding, pregnancy, miscarriages, use of oral contraceptives (OC) or HRT), medical history, and prognosis were evaluated with follow-up visits and/or telephonic calls. Continuous variables were investigated using the Mann–Whitney test, and factors associated with survival probability were evaluated using Cox's proportional hazards model, adjusting for potential confounders.

Results

228 PDAC women were analyzed, with mean age at diagnosis being 68. The most frequent stages were borderline resectable (35.9%) and locally advanced (25.4%), with a median overall survival (OS) of 14 months. The age of PDAC onset for patients with previous use of OC was significantly lower than that of non-users (63 years vs. 72; p<0.0001), and OC use was associated with a trend toward increased survival (HR 0.6; 95%CI: 0.35-1.03; p=0.06). In addition, previous use of HRT was associated with a reduced risk of recurrence or progression (HR, 0.4; 95%CI: 0.26-0.99; p=0.001). No differences in survival or progression-free probability were observed with the other factors.

Conclusion

This is the first study to evaluate whether gynecological/reproductive factors are associated with the prognosis of PDAC patients, with the use of OC and HRT being the most relevant factors. Previous OC users had a significantly lower onset age for PDAC and a borderline significant association was seen with increased survival. Additionally, HRT use is associated with a reduced risk of tumor recurrence or progression. These data need to be confirmed, and the potential mechanisms need to be elucidated.

Introduction

Diabetes mellitus (DM) is a substantial risk factor for pancreatic cancer (PC). Concurrently, aspirin has been implicated to have chemopreventive effect against cancer of digestive system. However, studies regarding the effect of aspirin on mitigating PC risk among DM populations remain scant.

Aims & Methods

We aimed to examine whether regular use of aspirin was associated with a reduced risk of PC after adjusting for known risk factors among type 2 diabetes (T2D) patients.

This was a territory-wide, retrospective cohort study of newly diagnosed T2D patients between 2001 and 2015 in Hong Kong. Exclusion criteria included <18 years old, history of PC, pancreatic neuroendocrine tumor, serous cystadenoma, chronic or acute pancreatitis, and pancreatic cyst. The outcome of interest was pancreatic cancer. Adjusted hazard ratios (aHRs) for outcomes associated with aspirin use were calculated using multivariable Cox regression models. Aspirin use was treated as a time-varying covariates (≥180 days use at each yearly interval) in the analysis to address and minimize immortal-time bias.

Results

We identified 342,920 T2D patients (52.2% male, mean age: 58.8±11.6 years), including 43,634 (12.7%) aspirin users. During a mean follow-up of 11.1±4.2 years, 1,114 (0.3%) patients developed PC, with an incidence rate of 2.92 per 10,000 person-years. Aspirin use was associated with a reduced PC risk (HR 0.55, 95%CI 0.46-0.66). When compared with the reference group (never use), a lower risk was observed with increasing frequency, with the exception of daily use. In addition, longer durations of aspirin use were associated with a progressively lower PC risks (HR 0.83, 95%CI 0.71-0.96, for less than five years of use; HR 0.56, 95%CI 0.45-0.69, for five to ten years of use; and HR 0.27, 95%CI 0.20-0.36, for ten or more years of use. Both frequency and duration of aspirin use demonstrated statistically significant trends (P_trend <0.001) (Table 1).

Table 1. HRs and 95% CIs for the association between frequency and duration of aspirin use and risk of pancreatic cancer

Aspirin use	No. of patients (n=342,920)	No. of PC (n=1,114)	HR (95% CI)	P*	Ptrend*
Frequency Never user	219,674	736	ref	-	<0.001
<Monthly use	13,809	52	0.66 (0.50-0.88)	0.004
Monthly to <weekly use	13.274	44	0.59 (0.43-0.80)	<0.001
Weekly to <daily use	73,232	201	0.54 (0.46-0.63)	<0.001
Daily use	22,931	81	0.90 (0.69-1.16)	0.401
Duration (years) Never user	219,674	736	ref	-	<0.001
<5	54,029	223	0.83 (0.71-0.96)	0.015
5 - <10	40,003	99	0.56 (0.45-0.69)	<0.001
≥10	29,214	56	0.27 (0.20-0.36)	<0.001

*Cox proportional hazards model was used to calculate the P values. Adjusted covariates included age, sex, lifestyle factors (body mass index, smoking, and alcohol use), metabolic disorders (dyslipidemia and hypertension), time-weighted mean HbA1c, DM complications, cardiovascular diseases, other anti-diabetic medications, non-aspirin non-steroidal anti-inflammatory drugs, and statins.
Abbreviation: CI, confidence interval; HR, hazard ratios; PC, pancreatic cancer; ref, reference

Conclusion

Aspirin use was associated with a reduction in PC risk among T2D patients, which was dependent on both frequency and duration of use. Notably, this trend was observed with increased frequency of use, with the exception of daily use. Further studies are warranted to assess long-term effects and potential risks.

Introduction

Contrast-enhanced endoscopic ultrasound (CEH-EUS) is a crucial imaging modality for evaluating focal pancreatic lesions. However, its interpretation often relies on subjective judgment and operator proficiency. Computer-aided color parametric imaging is a novel technique for contrast-enhanced endoscopic ultrasound that can highlight hemodynamic features of focal pancreatic lesions enabling a more objective assessment.

Aims & Methods

To explore the utility of ITM (Inflow-time Mapping)- a computer-aided color parametric imaging technique- in characterizing pancreatic focal lesions, identifying prognostic factors, and facilitating targeted management strategies in conjunction with CEH-EUS.

50 patients including 20 cases of pancreatic ductal adenocarcinomas (PDAC), 15 cases of chronic pancreatitis, 4 cases of pancreatic neuroendocrine tumors (NETs), 1 renal cell carcinoma metastasis, and 10 cystic lesions which include 2 mucinous cystadenomas (MCA), 2 serous cystadenomas (SCA), 4 pseudocysts and 2 intraductal papillary neoplasms were enrolled. All patients underwent CEH-EUS and ITM examinations of the frames obtained during the arterial phase. Before establishing the optimal starting frame for the ITM examination, a quantitative analysis was conducted on each CEH-EUS recording. Regions of interest (ROIs) were strategically positioned in either adjacent parenchyma or vascular structures. Subsequently, parameters derived from time-intensity curve (TIC) analysis, notably arrival time (AT), were estimated.
A retrospective review of CEH-EUS and ITM images involved assigning two criteria sets: (1) Routine CEH-EUS, focusing on enhancement degree and pattern, and (2) Combined CEH-EUS and ITM, emphasizing differentiation of pancreatic lesions based on contrast agent uptake speed compared to adjacent tissue. The final diagnosis was based on EUS-guided tissue acquisition.

Results

31 pancreatic lesions were initially considered PDAC based on their hypoenhanced appearance on CEH-EUS. ITM analysis could not provide additional information in 17 patients due to insufficient vascularization, while in 3 cases, ITM showed large intralesional vessels suggesting vascular invasion, supporting the PDAC diagnosis. In 11 patients, by showing no difference in the speed of UCA uptake in the enhanced regions of the lesion compared to the surrounding parenchyma, ITM analysis was able to correctly identify chronic pancreatitis, as proven by histology. In 4 patients, both CEH-EUS and ITM were consistent regarding the diagnosis of chronic pancreatitis. ITM analysis was able to provide an extensive characterization of the 4 pancreatic NETs by showing a greater speed of UCA uptake in the lesion and a centrifugal pattern of the parametric map for well-differentiated NETs. A centripetal, faster uptake of the UCA was noted in the case of pancreatic metastasis. ITM analysis also proved useful in objectively highlighting the speed and pattern of enhancement (septal/mural) of the cystic lesions included, particularly for SCAs.

Conclusion

In patients with chronic pancreatitis, where parenchymal inhomogeneity and altered local perfusion might influence the purely visual assessment, ITM complements CEH-EUS, potentially reducing unnecessary biopsies and enabling follow-up care. Additionally, for hypervascular pancreatic lesions, ITM aids in both differential diagnosis and prognostic assessment. Intralesional vessels noted on ITM images should be carefully assessed since vascular invasion can serve as an indirect marker for malignancy, particularly in hypoenhanced lesions.

Introduction

Besides stage, age and CA19-9 there is limited knowledge on “patient-related factors” associated with chemotherapy response for Pancreatic Ductal Adenocarcinoma (PDAC) patients. Smoking worsens chemotherapy response in other tumours and seems to promote tumor progression in PDAC preclinical models, but data in human PDAC are scanty.

Aims & Methods

PDAC patients were prospectively enrolled at diagnosis with exposome and clinical data registered, and tumors sampled for research purpose during Endoscopic Ultrasound (EUS). Patients were then followed-up to register chemotherapy treatment [whether Folfirinox (F), Abraxane-gemcitabine (AG) or a combination of cisplatin, abraxane, capecitabine and gemcitabine (PAXG)] and evaluate disease control rate (DCR) at 6-months (DCR-6), Progression-Free-Survival (PFS) and Overall-Survival (OS). We also explored transcriptomic signatures associated with smoking on a subset of EUS-acquired PDAC samples undergoing RNA-sequencing, with differential gene expression (DGE) analysis and pathways analysis performed. Furthermore, in vitro analyses with PDAC cell lines CAPAN-1 were treated with Folfirinox or gemcitabine with/without the nicotine compound 4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone to evaluate in vitro effects.

Results

326 patients treated with chemotherapy of interest were analyzed. Median age was 65, with 51.5% being males. Disease’s resectability at diagnosis was 10.4% resectable, 37.7% borderline-resectable, 26.9.% locally-advanced, 24.8% metastatic. AG was used in 42.3% of patients, PAXG in 25.7%, Folfirinox in 31.9%. DCR-6 was 57.9% in current smokers vs 70.4% in never-/ex-smokers (p=0.05). Current smoking was associated with a lack of DCR-6 at adjusted multivariable analysis (OR=1.99; 95%CI:1.1-3.5; p=0.01). At subgroup analysis, this was confirmed only for Folfirinox patients, with DCR-6 being 46.2% for current smokers vs 75.6% for non-current smokers(p=0.007). Current smokers had a significantly shorter PFS (5 vs 13 months; HR:1.79; 95%CI:1.13-3.21; p=0.01) and OS (24 vs 34; HR 1.93; 95%CI: 1-3.67; p=0.04) compared to non-smokers at adjusted multivariable analysis.
At transcriptomic analysis on a subset of 84 patients, current smokers were more prevalent in patients developing the more aggressive basal-like subtype (50% vs 15%; p=0.03), had lower expression of the classical marker GATA6 (3.27 vs 3.92; p=0.03) as also different activated pathways such as activated MAPK signalling, Axon guidance, Hypoxia and epithelial-mesenchymal-transition signalling among the others.
At in vitro experiments, for cell survival analysis, CAPAN-1 PDAC cells showed a significant reduced response to Folfirinox treatment when treated in combination with nicotin compounds, which was not observed for gemcitabine alone or in combination.

Conclusion

Collectively, our results consistently point towards a deleterious effect of smoking on response to Folfirinox regimen. Clinical data show that current smoking is a predictive factor for lower DCR-6, shorter PFS and OS; transcriptomic analyses show different gene expressions between smokers and non-smokers, with a transition toward reduced expression of classical phenotype and activation of inflammatory and pro-mesenchimal pathways. In vitro experiments support the negative effect of smoking on the response to Folfirinox. Smoking should be considered as a covariate to be investigated when choosing chemotherapy regimens in patients with PDAC, and patients should be discouraged to continue smoking.