Introduction

The early diagnosis of pancreatic cancer has long been considered a major clinical challenge. Recently in Japan, imaging-based screening strategies focusing on indirect findings have ushered in a new era, enabling the detection of carcinoma in situ and high-grade pancreatic intraepithelial neoplasia (PanIN). This study aimed to elucidate the molecular evolutionary mechanisms of PanIN development and progression.

Aims & Methods

We conducted detailed histopathological analysis and multi-regional genomic sequencing on 33 lesions obtained from a single patient with a family history of pancreatic cancer. The patient initially underwent distal pancreatectomy for a branch duct-type intraductal papillary mucinous neoplasm (IPMN) accompanied by adjacent main pancreatic duct (MPD) stenosis, followed by remnant pancreatectomy four years later due to newly detected ductal irregularities. The analyzed lesions included 15 low-grade PanINs, 14 high-grade PanINs, two low-grade IPMNs, and two concomitant pancreatic ductal adenocarcinoma components. Molecular analyses included KRAS and GNAS mutation detection using droplet digital PCR, targeted sequencing using a pancreatic cancer-related gene panel, and whole-exome sequencing. Tumor phenotypes were assessed by immunohistochemistry.

Results

Among numerous low-grade PanINs harboring various KRAS mutations, four distinct multicentric high-grade PanINs arose in the pancreatic body and tail. These included a laterally spreading high-grade PanIN within the stenotic MPD, characterized by KRAS G12D, TP53 deletion, and GATA6 Y83TfsX54; and three discrete high-grade PanINs located in branch ducts, all harboring KRAS G12V accompanied respectively by TP53 Y107D; TP53 S241F and ARID1A Q386X and S2096X; and TP53 G245S and ARID1A Q1066X. A low-grade gastric-type IPMN harboring KRAS G12R was determined to be clonally independent from the adjacent high-grade PanINs. A low-grade PanIN with KRAS G12D was identified at the pancreatic cut margin, though it showed no evidence of malignancy. In the remnant pancreatic head, a high-grade PanIN harboring KRAS G12D, TP53 deletion, and GATA6 Y83TfsX54—identical to the dominant clone in the pancreatic body—had extended along the MPD from the ductal stump to the ampulla. Two small invasive carcinoma foci were found to be continuous with this high-grade PanIN and shared identical KRAS, TP53, and GATA6 mutations, along with additional copy number variations affecting several genes. Another small high-grade PanIN with KRAS G12D and TP53 C275Y was identified in a neighboring branch duct. Furthermore, a germline CDKN2A H66R variant was detected, suggesting a potential hereditary predisposition to pancreatic tumorigenesis. The patient has remained recurrence-free for four years following the remnant pancreatectomy.

Conclusion

In high-risk individuals with a family history of pancreatic cancer or IPMN, PanINs may develop in large numbers, and multiple carcinomas in situ can arise simultaneously. Among these, clones exhibiting pronounced intraductal proliferation or progression toward invasion—thereby impacting clinical outcomes—may be selectively favored. This study provides novel insights into the clonal selection and molecular progression of multicentric high-grade PanINs. To our knowledge, this is the first report to comprehensively delineate the molecular trajectory of multifocal high-grade PanINs in a high-risk patient.

Introduction

The rise in obesity rates has triggered a surge in associated health issues, with metabolic syndrome (MS) affecting approximately 25% of populations in Western countries. Severe acute pancreatitis (AP) is associated with mortality rates as high as 50%. Prior research has linked components of MS to heightened complications and mortality in cases of AP.

Aims & Methods

This meta-analysis aims to elucidate potential risk factors and their combined effects on the outcomes of AP. We performed a systematic search of PubMed, Embase, and the Cochrane Library until November 1, 2023, identifying studies based on specified criteria. We investigated the influence of MS and its components (obesity, hypertension, diabetes mellitus, and hypertriglyceridemia) on AP outcomes, calculating pooled odds ratios (OR) with 95% confidence intervals (CIs). The study protocol was registered with PROSPERO under the identifier CRD42023471092.

Results

From an initial 15,904 records, 93 studies were included in the analysis. Overweight and obesity emerged as significant risk factors for complications (local OR: 2.677, 95%CI: 1.421-5.044; systemic OR: 2.404, 95%CI: 1.481-3.901) and the severity of AP (BMI≥30 kg/m², OR: 3.058, 95%CI: 1.369-6.829). Elevated triglyceride levels were linked to ICU admissions (OR: 2.546, 95%CI: 1.529-4.237) and severe AP (OR: 2.372, 95%CI: 1.275-4.413); hypertension correlated with increased mortality (OR: 2.135, 95%CI: 1.870-2.437), while diabetes was associated with higher odds of ICU admission (OR: 1.645, 95%CI: 1.358-1.992) and severe AP (OR: 1.49, 95%CI: 1.09-2.03). Our findings suggest that MS may elevate the likelihood of severe AP (OR=1.398, 95%CI: 0.918-2.129).

Conclusion

The individual components of metabolic syndrome are significant risk factors for complications, severity, and mortality related to acute pancreatitis. It is imperative to prioritize lifestyle counseling, education, and effective management for patients dealing with obesity.

Introduction

Advanced pancreatic cancer (PC) continues to be associated with a poor prognosis, where the occurrence of pancreatic exocrine insufficiency frequently leads to malnutrition and deteriorating nutritional status. Traditional laboratory markers, such as lymphocyte count and serum albumin levels, are commonly employed to assess nutritional status; however, integrated nutritional indices like the Prognostic Nutritional Index (PNI) have emerged as significant prognostic indicators in various malignancies. Notably, a low PNI has been identified as a predictor of postoperative complications following the Whipple procedure in pancreatic cancer patients and significantly correlates with overall survival among individuals with advanced PC. While the Nutritional Risk Index (NRI) has been evaluated in other cancer types, its application in advanced pancreatic cancer remains underexplored.

Aims & Methods

This study aims to evaluate the prognostic value of PNI and NRI in patients with advanced pancreatic cancer.
A retrospective analysis was conducted on electronic medical records of 158 patients diagnosed with advanced pancreatic cancer who were initiating chemotherapy. PNI and NRI were computed using standard parameters, and baseline levels were compared between patients with proximal and distal tumor locations. Among 125 patients commencing FOLFIRINOX chemotherapy, baseline PNI and NRI were analyzed in relation to outcomes at the 12-week follow-up, categorizing patients into groups based on mortality (n=21), disease progression (n=51), and disease stabilization (n=53). Statistical differences between high and low nutritional index groups were assessed using the log-rank test, and both univariate and multivariable analyses were conducted to identify risk factors associated with mortality within three months post-chemotherapy initiation.

Results

The analysis revealed that patients with tumors located in the pancreatic head exhibited significantly lower PNI (40.11 vs. 42.01, p=0.002) and NRI (104.30 vs. 110.06, p=0.004) compared to those with distal tumors. In the FOLFIRINOX subgroup, a significant decrease in PNI (39.51 vs. 41.51 and 41.82, p=0.044) was observed among those who deceased by the first follow-up, while NRI did not show similar significance. Univariate analysis identified a PNI cut-off of 40.25 (HR 2.514; 95% CI: 1.025-6.169, p=0.044) and an NRI threshold below 105.6 (HR 2.75; 95% CI: 1.039-7.277, p=0.042) as independent prognostic factors. However, in multivariable analysis, the presence of two or more metastatic sites beyond the primary tumor was the only factor significantly related to mortality risk by the follow-up (HR 7.21; 95% CI: 2.02-25.738, p=0.002).

Conclusion

Our findings underscore the relationship between PNI and NRI with nutritional status, asserting their utility as predictive tools for survival in patients with advanced pancreatic cancer initiating chemotherapy.

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is characterized by very poor 5-year survival of only 8-12% due to a late diagnosis and a highly desmoplastic environment, limiting therapeutic options [1]. Current treatment options for PDAC patients are mostly restricted to chemotherapy followed by surgery or palliative care [2]. These treatments have limited efficacy and are accompanied by severe side effects, strongly affecting the quality of life of these patients. Recent advances in nanotechnology have optimized targeted drug delivery in tumors with high stromal density by improving intratumoral drug retention, enhancing local drug concentrations, and thereby boosting treatment efficacy and potentially reducing side effects [3-6]. This would enable an efficient endoscopic delivery of a local depot of concentrated chemotherapy.

Aims & Methods

Here we investigated the preclinical efficacy and tolerability of a novel thermosensitive hydrogel, ChemoGell (CG), loaded with gemcitabine in preclinical human and mouse PDAC models. To evaluate the efficacy of CG, in vitro experiments using patient-derived organoids and PDAC explants were performed. This was further explored in vivo by using a human patient-derived xenograft (PDX) and the syngeneic KPC3 mouse model. Two intratumoral injections with saline, CG and gemcitabine-loaded CG (CG-Gem) were performed in both PDX and KPC3 models and compared to systemic gemcitabine administration. To evaluate potential off-target effect, other vital organs and haematological toxicity related to gemcitabine were evaluated.

Results

Both CG and CG-Gem were safe and well-tolerated in vivo. Upon CG-Gem, both in vitro and in vivo models showed strongly increased cytotoxicity compared to unloaded CG and control groups. Remarkably, we were able to inject a much higher dose (~125x) intratumorally compared to systemic gemcitabine dose. By increasing gemcitabine cytotoxicity, locally treated mice showed a significant improved survival. In a human PDX model, complete survival of mice (100%) was observed compared to control groups in which all reached humane endpoint. Given the enhanced treatment efficacy, we are currently investigating the role of the tumor microenvironment, particularly looking at stromal and immune cell dynamics. Interestingly, preliminary data shows that CG-Gem depots are surrounded and/or infiltrated with fibroblasts, macrophages, and other immune cells. To reveal the mechanism behind, further experiments looking at the different cell subtypes are undergoing.

Conclusion

Our findings represent a potential strategy for integrating localized (endoscopic) and systemic treatment modalities, addressing critical challenges in hard-to-treat PDAC management, and improving patient prognosis through more effective and targeted therapeutic strategies.

References

1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229-263.
2. Conroy T, Pfeiffer P, Vilgrain V, Lamarca A, Seufferlein T, O’Reilly EM, et al. Pancreatic cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Annals of Oncology. 2023/11/01;34(11).
3. Ramazani F, Nostrum CFv, Storm G, Kiessling F, Lammers T, Hennink WE, et al. Locoregional cancer therapy using polymer-based drug depots. Drug Discovery Today. 2016/04/01;21(4).
4. Luo W, Zhang T. The new era of pancreatic cancer treatment: Application of nanotechnology breaking through bottlenecks. Cancer Letters. 2024/07/10;594.
5. Jiang Z, Fu Y, Shen H. Development of Intratumoral Drug Delivery Based Strategies for Antitumor Therapy. Drug Design, Development and Therapy. 2024 Dec 31:2189-202.
6. Rossi SM, Ryan BK, Kelly HM. Evaluation of the activity of a chemo-ablative, thermoresponsive hydrogel in a murine xenograft model of lung cancer. British Journal of Cancer 2020 123:3. 2020-05-27;123(3).

Disclosure

Helena Kelly is a named inventor on granted patent US20230126053 ‘Thermo-responsive hydrogel for intratumoral administration as a treatment in solid tumor cancers’ and is also co-founder and CSO of OncoLize LLC. Mike de Leeuw is co-founder and CEO of OncoLize LLC. Tushar Tomar is drug development director of OncoLize LLC. This work was supported by a research grant from OncoLize to LH.

Introduction

Intraductal papillary mucinous neoplasms (IPMNs) are increasingly diagnosed due to rising life expectancy and widespread use of abdominal imaging. Despite the publication of several guidelines to drive the management of IPMNs, a significant proportion of patients still undergo surgical resection for lesions ultimately classified as low-grade dysplasia (LGD), while others managed conservatively may progress to invasive carcinoma (IC). Pancreatic surgery could have high perioperative morbidity and mortality, highlighting the need for improved preoperative stratification. Among the available tools, endoscopic ultrasound with fine-needle aspiration (EUS-FNA) represents a key diagnostic method for assessing the risk of malignancy in IPMN.

Aims & Methods

This study aimed to evaluate the diagnostic accuracy of EUS-FNA in predicting histological dysplasia grade in surgically resected IPMNs. We retrospectively included patients who underwent both EUS-FNA and surgery at San Raffaele Hospital. Surgical diagnoses were classified into LGD, high-grade dysplasia (HGD), or IC, while cytological diagnoses also included “Negative for malignant cells” (NMC). We defined STRICT criteria (SC) as exact cytological-histological concordance (considering NMC as non-concordant), while LARGE (LC) considered NMC equal to LGD. Concordance was assessed using Fleiss’ kappa (κ) and linear weighted κ. Uni- and multivariate logistic regressions were conducted to identify predictors of concordance. Diagnostic performance of EUS cytology in distinguishing LGD and HGD/IC was evaluated through sensitivity, specificity, PPV, NPV, and accuracy. A Random Forest classifier was developed to predict concordance before FNA utilizing three variables: patient age, main pancreatic duct (MPD) dilation, and IPMN subtype. The model was trained on the entire dataset with 100 decision trees and a fixed random state to ensure reproducibility.

Results

Ninety-four patients were included (36% branch duct-, 41% main duct-, 23% mixed type-IPMN). The concordance using SC and LC criteria was moderate (Fleiss’ κ respectively 0.41 and 0.36). The weighted κ was 0.55. When stratified, concordance was κ=0.52 for LGD 0.437 for IC, and 0.109 for HGD. Univariate analysis identified diffuse MPD dilation (p=0.0016 SC, p=0.0002 LC), cyst wall enhancement (p=0.0955 SC), grade of dysplasia (p=0.0809 SC, <0.00001 LC), and IPMN subtype (p=0.0433 LC) as significant. Multivariate analysis confirmed cyst wall enhancement (OR=0.128, p=0.0334) and grade of dysplasia (OR=0.239, p=0.0094) as independent predictors using SC, while the latter one alone (OR=0.354, p=0.0027) when LC were considered. Diagnostic performance of EUS cytology in distinguishing LGD vs HGD/IC showed sensitivity 75%, specificity 89.2%, PPV 93.1%, NPV 64.7%, accuracy 79.8%. The Random Forest model demonstrated high predictive performance, achieving an accuracy of 94.7% and an area under the receiver operating characteristic curve (AUC) of 0.99. It correctly classified 89 out of 94 cases, with 4 false negatives and 1 false positive. Precision and recall were 97.9% and 92.3% for the concordant class.

Conclusion

EUS-FNA shows moderate concordance with final pathology, especially for LGD and IC, while HGD remains challenging. Pre-FNA imaging features are predictive of concordance. A machine learning model demonstrated high accuracy using preprocedural variables only, supporting its clinical value in biopsy guidance. Strengths include the high-volume pancreatic center setting. Limitations include selection bias from a surgical cohort, which is inherent to histology-based studies.

Introduction

The prognosis for patients with advanced pancreatic cancer (PC) remains exceptionally bleak, with a 5-year survival rate estimated at just 4%. This condition is frequently accompanied by pancreatic exocrine insufficiency, which contributes to malnutrition and a significant decline in nutritional status. While conventional laboratory markers such as serum albumin and lymphocyte counts are commonly employed to assess nutritional health, integrative nutritional indices have emerged as meaningful prognostic indicators across various malignancies. Specifically, the hemoglobin, albumin, lymphocytes, and platelets index (HALP) has shown promise in predicting overall survival in cancer cohorts. However, other indices, such as the prognostic immune nutritional index (PINI), have yet to be examined in the context of pancreatic cancer.

Aims & Methods

Aim: This study aims to assess the prognostic value of the HALP and PINI in patients with advanced pancreatic cancer.
A retrospective analysis was conducted utilizing electronic medical records from 158 patients diagnosed with advanced pancreatic cancer who had begun treatment. Conventional parameters were employed to calculate HALP and PINI levels, which were then compared between patients with proximal and distal tumor locations prior to the initiation of chemotherapy. Within a subgroup of 125 patients receiving FOLFIRINOX, baseline HALP and PINI values were analyzed in relation to outcomes categorized into three groups at the 12-week follow-up: mortality (n=21), disease progression (n=51), and disease stabilization (n=53). The log-rank test was utilized to evaluate statistical differences between high and low nutritional index groups. Univariate and multivariable analyses were performed to identify risk factors for mortality within three months of chemotherapy initiation.

Results

Among the 158 patients included in the analysis, those with tumors located in the pancreatic head exhibited significantly lower HALP (32.34 vs. 43.05, p=0.021) and PINI (3.23 vs. 3.48, p=0.003) compared to patients with distal tumors. In the FOLFIRINOX subgroup, HALP levels were significantly lower in individuals who deceased by the first follow-up (25.76 vs. 36.115 and 41.8, p=0.041), while PINI did not demonstrate a similar relationship. Univariate analysis revealed that a HALP value below 26.85 (HR 2.548; 95% CI: 1.021-6.357, p=0.045) and a PINI below 3.26 (HR 3.49; 95% CI: 1.31-9.299, p=0.012) were independent predictors of mortality. In multivariate analysis, the presence of two or more metastatic sites beyond the primary tumor was the sole factor associated with a heightened risk of death at the first follow-up (HR 7.21; 95% CI: 2.02-25.738, p=0.002).

Conclusion

Our findings support the notion that HALP and PINI are closely related to nutritional status and serve as independent risk factors for mortality within three months of initiating chemotherapy in patients with advanced pancreatic cancer.