Targeting the NPY/NPY1R signaling axis in mutant p53-dependent pancreatic cancer impairs metastasis.Science advances • March 12, 2025
Cecilia Chambers, Supitchaya Watakul, Peter Schofield, Anna Howell, Jessie Zhu, Alice M Tran, Nadia Kuepper, Daniel Reed, Kendelle Murphy, Lily Channon, Brooke Pereira, Victoria Tyma, Victoria Lee, Michael Trpceski, Jake Henry, Pauline Melenec, Lea Abdulkhalek, Max Nobis, Xanthe Metcalf, Shona Ritchie, Antonia Cadell, Janett Stoehr, Astrid Magenau, Diego Chacon Fajardo, Jessica Chitty, Savannah O'connell, Anaiis Zaratzian, Michael Tayao, Andrew Da Silva, Ruth Lyons, Leonard Goldstein, Ashleigh Dale, Alexander Rookyard, Angela Connolly, Ben Crossett, Yen T Tran, Peter Kaltzis, Claire Vennin, Marija Dinevska, Anubhav Mittal, Robert Weatheritt, Andrew Philp, Gonzalo Del Monte Nieto, Lei Zhang, Ronaldo Enriquez, Thomas Cox, Yan-chuan Shi, Mark Pinese, Nicola Waddell, Hao-wen Sim, Tatyana Chtanova, Yingxiao Wang, Anthony Joshua, Lorraine Chantrill, Thomas R Evans, Anthony Gill, Jennifer Morton, Marina Pajic, Daniel Christ, Herbert Herzog, Paul Timpson, David Herrmann
Pancreatic cancer (PC) is a highly metastatic malignancy. More than 80% of patients with PC present with advanced-stage disease, preventing potentially curative surgery. The neuropeptide Y (NPY) system, best known for its role in controlling energy homeostasis, has also been shown to promote tumorigenesis in a range of cancer types, but its role in PC has yet to be explored. We show that expression of NPY and NPY1R are up-regulated in mouse PC models and human patients with PC. Moreover, using the genetically engineered, autochthonous KPR172HC mouse model of PC, we demonstrate that pancreas-specific and whole-body knockout of Npy1r significantly decreases metastasis to the liver. We identify that treatment with the NPY1R antagonist BIBO3304 significantly reduces KPR172HC migratory capacity on cell-derived matrices. Pharmacological NPY1R inhibition in an intrasplenic model of PC metastasis recapitulated the results of our genetic studies, with BIBO3304 significantly decreasing liver metastasis. Together, our results reveal that NPY/NPY1R signaling is a previously unidentified antimetastatic target in PC.
Overcoming therapy resistance in pancreatic cancer: challenges and emerging strategies.Advanced Drug Delivery Reviews • April 11, 2025
Taymin Du Toit Thompson, Lionel Leck, Josef Gillson, Nick Pavlakis, Anthony Gill, Jaswinder Samra, Anubhav Mittal, Sumit Sahni
Pancreatic cancer (PC) is one of the deadliest types of cancer, with a 5-year survival rate of ∼12.5 %. It is expected to become the second leading cause of cancer-related deaths by 2030. Despite recent advances in treatment options by advent of various targeted and immunotherapies, their benefits have not been actualized for PC patients and chemotherapy remains the mainstay systemic therapeutic option for these patients. However, the majority of PC tumours have a highly chemo-resistant phenotype, leading to therapeutic failure. This review provides a comprehensive overview of the established mechanisms related to chemoresistance in PC and provides insight into emerging theories, including the potential role of the microbiome in modulating therapeutic responsiveness. It further discusses potential opportunities to explore to overcome this critical clinical problem.
An international inter-rater agreement study in the challenging diagnosis of squamous dysplasia of the oesophagus. Histopathology • March 25, 2025
Ameya Patil, Tracy Jiezhen, Heidi Kosiorek, Ian Brown, Fátima Carneiro, Anthony Gill, Priyanthi Kumarasinghe, Ryoji Kushima, Kieran Sheahan, Neil Shepherd, Tomas Slavik, Amitabh Srivastava, Gregory Lauwers, Cord Langner, Rish Pai
Objective: There is a lack of published literature on the diagnostic reproducibility of oesophageal squamous dysplasia using a two-tiered grading system.
Results: We identified 75 oesophageal biopsies, which were reviewed by 10 international pathologists twice (1500 total observations) with a > 4-week washout period. Between rounds, a consensus meeting refining diagnostic criteria was held and an atlas was created to provide illustrations. Overall agreement was fair with kappa of 0.35 and 0.32 in round 1 and 2, respectively. Agreement was moderate to fair for negative for dysplasia (ND) (round 1 = 0.41 and round 2 = 0.34) and poor for indefinite for dysplasia (IND) and low-grade dysplasia (LGD) (kappa <0.2). Agreement for high-grade dysplasia (HGD) was good in both rounds (round 1 = 0.64; round 2 = 0.61). In round 1, majority diagnosis (MDx, ≥6 of 10 raters agreeing) was seen in 51 (68%) cases with the majority classified as ND (N = 27) or HGD (N = 18). MDx was rarely achieved for LGD (N = 6). In round 2, MDx was seen in 49 (65%) cases (20 ND, 1 IND, 11 LGD and 17 HGD). Of the 40 cases with MDx for both rounds, 39 were concordant (15 HGD, 6 LGD and 18 ND).
Conclusions: Overall agreement among pathologists in diagnosing squamous lesions is fair; however, HGD had good agreement. This study fills an important gap in our knowledge of the inter-rater variability in the diagnosis of oesophageal squamous dysplasia.
Succinate dehydrogenase deficient renal cell carcinoma frequently expresses GATA3 and L1CAM.Virchows Archiv : An International Journal Of Pathology • February 13, 2025
Ankur Sangoi, Sean Williamson, Murat Oktay, Anthony Gill, Kiril Trpkov, Farshid Siadat, Fiona Maclean, Laurence Galea, Deniz Baydar, Caglar Cakir, Yasemin Karabulut, Deniz Baycelebi, Ganime Coban, Banu Sarsik, Busra Bayrak, Levente Kuthi, Boglarka Posfai, Aysha Mobeen, Sambit Mohanty, Xulang Zhang, Mohammed Alghamdi, Liang Cheng, Michelle Hirsch, Mahmut Akgul
Succinate dehydrogenase deficient renal cell carcinoma (SDH RCC) is an uncommon, familial RCC that has overlapping morphologic features with other low grade eosinophilic tumors of the kidney. Although the diagnosis of SDH RCC relies on loss of SDHB by immunohistochemistry (IHC), not all laboratories have access to this antibody. GATA3 and L1CAM are increasingly utilized in the diagnosis of eosinophilic renal tumors; however, their expression profile has not been studied in SDH RCC. We evaluated clinical parameters and GATA3 and L1CAM reactivity in a large nephrectomy cohort (n = 40) of patients with SDH RCC. The male-to-female ratio was 3:1 and the median age was 48 years (range: 17 to 79 years). Specimens included 20 radical resections, 19 partial resections, and 1 unknown procedure. Tumor laterality was nearly equal (right:left = 18:20; one case was bilateral). Tumors in 4 (10%) patients were multifocal. Median tumor size was 2.0 cm (range 1 - 14.8 cm). Tumor stage distribution was: pT1a (n = 16, 40%), pT1b (n = 7, 18%), pT2a (n = 5, 13%), pT2b (n = 4, 10%), pT3a (n = 6, 15%), and pT4 (n = 1, 3%). Most cases (n = 33, 83%) exhibited classical morphologic features, whereas 2/40 (5%) had sarcomatoid differentiation. GATA3 was positive in 37/39 (95%) tumors, with more than 50% of cells positive in 35/37 (95%), and with moderate-high intensity (2/3 +) in 33/37 (89%). L1CAM was expressed in 13/18 (72%) tumors, with moderate-high intensity (2/3 +) in 10/13 (77%). When both markers were performed, dual GATA3/L1CAM expression was present in 12/17 (71%) tumors. As L1CAM has been postulated to represent a marker of principal cell of the distal nephron, frequent L1CAM expression in SDH RCC suggests that they may originate from the principal cells of the distal nephron.
Adjuvant External Beam Radiotherapy Reduces Local Recurrence in Poorly Differentiated Thyroid Cancer : A Multicenter Retrospective Cohort Study Describing Outcomes in the Treatment of Resectable Poorly Differentiated Thyroid Cancer. Annals Of Surgical Oncology • February 03, 2025
Pascal K Jonker, Jan Koetje, John Turchini, Jia Feng Lin, Anthony Gill, Thomas Eade, Ahmad Aniss, Roderick Clifton Bligh, Bettien Van Hemel, Diana Learoyd, Hans H Verbeek, Thera Links, Bruce Robinson, Venessa Tsang, Stanley Sidhu, Schelto Kruijff, Mark Sywak
Background: Poorly differentiated thyroid carcinoma (PDTC) accounts for 5% of all thyroid cancers and is responsible for a large proportion of thyroid cancer-related deaths. The optimal treatment approach is not clear. This study aimed to evaluate the effect of postoperative intensity-modulated radiotherapy (IMRT) on the treatment of resectable PDTC. Additionally, treatment-related morbidity, characteristics of 131I-refractory disease, and factors affecting survival were assessed.
Methods: The study included consecutive PDTC cases from 1997 to 2018, defined according to Turin criteria and treated in two tertiary referral centers. Surgery, IMRT, 131I, and systemic therapies were administered based on multidisciplinary team recommendations. The primary study outcome was 5-year local control after IMRT in cases with positive resection margins (micro- and macroscopic). The secondary outcomes were treatment-related morbidity within 30-days after completion of treatment (Clavien-Dindo and Common Terminology Criteria for Adverse Events [CTC-AE] 5.0), 131I-refractory disease characteristics using standardized definitions, and factors influencing survival.
Results: Among 51 PDTC cases, 53% presented with metastatic disease. Adjuvant IMRT improved 5-year local control (100% vs. 17.5%; p = 0.02), with a higher number of grades 1 to 3 complications (p = 0.005) versus cases without IMRT. Within 13 months, 131I-refractory disease occurred in 62.7% of the patients and was more common in non-survivors (86.6% vs. 52.8%; p = 0.01). Positive resection margins and extrathyroidal extension were associated with poor survival in the univariate analysis, but were not significant in the multiple regression analysis.
Conclusions: Adjuvant IMRT may reduce thyroid bed recurrence in resectable PDTC with positive resection margins, but is associated with increased treatment-related complications. 131I-refractory disease occurs frequently, with non-survivors progressing earlier to 131I resistance.
