P-P11 A tumour responsive, oxygen-generating nanoparticle to combat hypoxia in pancreatic tumours

Background Pancreatic cancer remains a significant therapeutic challenge and its poor prognosis has remained relatively unchanged for the past 40 years. Pancreatic tumours are highly desmoplastic and impenetrable lesions in which both gas and mass transfer is severely compromised. This leads to the development of hypoxia within the tumour and this compromises therapeutic approaches that rely on cytotoxic reactive oxygen species, e.g. photodynamic therapy, sonodynamic therapy and radiotherapy. Hypoxia also results in a relatively low pH within the tumour microenvironment. Here we describe a pH sensitive nanoparticle that can generate oxygen in the tumour and enhance ROS generating therapeutic approaches. Methods CaO2 NPs were generated by exposing to low frequency ultrasound and subsequently coated using a polymethacrylate polymer that becomes soluble at pH 6.4. For some studies, the sonosensitiser, Rose Bengal was attached to the particles. Oxygen generation in tumours (BxPC3) was demonstrated by inserting a dissolved oxygen probe into tumours following IV administration of particles. Particles were also employed together with photodynamic therapy (PDT) and sonodynamic therapy (SDT) using human xenograft and syngeneic pancreatic tumour models. In some cases, tumour tissues were recovered and analysed for tumour infiltrating immune cells using flow cytometry. Results Conclusions Coating CaO2 nanoparticles with a pH sensitive polymer provides in situ oxygen generation in tumours. Transient provision of oxygen enhances therapies that depend on the generation of cytotoxic reactive oxygen species. When used with SDT, and using a bilateral syngeneic pancreatic tumour model, a powerful abscopal effect was observed and this was shown to be immune-mediated. The above data suggest that the particles may be exploited to enhance other therapies that depend on the generation of ROS, e.g. radiotherapy, and further suggest that the approach can be used to treat either local or disseminated forms of pancreatic cancer.

ALDOA inhibits cell cycle arrest induced by DNA damage via the ATM-PLK1 pathway in pancreatic cancer cells

Background ALDOA is a glycolytic enzyme found mainly in developing embryos, adult muscle and various malignant tumours, including pancreatic tumours. Our previous study revealed that ALDOA, an oncogene, can promote the proliferation and metastasis of pancreatic tumours. Furthermore, ALDOA could predict poor prognosis in patients with pancreatic tumours. Methods IHC analysis of PDAC tissues was conducted. Western blotting, PCR, cellular IF experiments and cell cycle assessment were conducted utilizing cell lines. GSEA and KEGG pathway analysis were used to identify potential downstream pathways. Results To explore the effects of ALDOA on the occurrence and development of pancreatic tumours, we analysed the RNA sequencing results and found that ALDOA could inhibit the DDR. Under normal circumstances, when DNA is damaged, initiation of the DDR causes cell cycle arrest, DNA repair or cell apoptosis. Further experiments showed that ALDOA could inhibit DNA repair and reverse cell cycle arrest induced by DNA damage so that DNA damage persisted to promote the occurrence and progression of cancer. Conclusions Regarding the molecular mechanism, we found that ALDOA inhibited the DDR and improved activation of the cell cycle checkpoint PLK1 by suppressing ATM, which promotes tumour cell progression. Consequently, ALDOA has a profound effect on pancreatic cancer development.

Rare Pseudopapillary Neoplasm of the Pancreas: A 10-Year Experience

Introduction. The solid pseudopapillary epithelial neoplasm (SPN) is a rare form of pancreatic neoplasm with an incidence of 2-3% of all pancreatic tumours. The recent increase in incidence is attributed to the increasing use of imaging techniques for nonspecific abdominal complaints. We report our institutional experience in the management of this tumour over the last decade. Method. We retrospectively analyzed from a prospectively maintained database of patients from January 2011 to December 2020 who were operated upon for SPN. All the patients were followed till date. Results. Of 479 patients operated on for various types of pancreatic tumours during this period, 15 (3.1%) had SPN. The mean age of presentation was 28 years with a female preponderance (12/15, 80%). The most common location was the body and tail of the pancreas (66%), and the mean size was 6.4 cm (2–15 cm). The tumour extent was defined as ‘borderline resectable’ in 20% of cases. Distal pancreatectomy was done in 11 patients with spleen preservation in 3. R0, R1, and R2 resection were done in 12, 2, and 1 patient(s), respectively. The operative mortality was 6.7%. All the patients are doing well on follow-up. Conclusion. SPN is a low-grade malignant tumour with a strong female predilection. Clinical manifestations have no specificity, imaging examination only contributes tumour location, and the final diagnosis rests on pathology. Surgery is the main modality of treatment and carries a good prognosis.