Pancreatic ductal adenocarcinoma (PDAC) represents a formidable challenge due to its aggressive nature and poor prognosis. The tumor microenvironment (TME) in PDAC, characterized by intense stromal desmoplastic reactions and a dominant presence of cancer-associated fibroblasts (CAFs), significantly contributes to therapeutic resistance. However, within the heterogeneous CAF population, fibroblast activation protein (FAP) emerges as a promising target for Gallium-68 FAP inhibitor positron emission tomography (Ga68FAPI-PET) imaging. Notably, 68Ga-FAPI-PET demonstrates promising diagnostic sensitivity and specificity, especially in conjunction with low tracer uptake in non-tumoral tissues. Moreover, it provides valuable insights into tumor–stroma interactions, a critical aspect of PDAC tumorigenesis not adequately visualized through conventional methods. The clinical implications of this innovative imaging modality extend to its potential to reshape treatment strategies by offering a deeper understanding of the dynamic TME. However, while the potential of 68Ga-FAPI-PET is evident, ongoing correlative studies are essential to elucidate the full spectrum of CAF heterogeneity and to validate its impact on PDAC management. This article provides a comprehensive review of CAF heterogeneity in PDAC and explores the potential impact of 68Ga-FAPI-PET on disease management.

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in oncology due to its advanced stage upon diagnosis and limited treatment options. Surgical resection, the primary curative approach, often results in poor long-term survival rates, leading to the exploration of alternative strategies like neoadjuvant therapy (NAT) and total neoadjuvant therapy (TNT). While NAT aims to enhance resectability and overall survival, there appears to be potential for improvement, prompting consideration of alternative neoadjuvant strategies integrating full-dose chemotherapy (CT) and radiotherapy (RT) in TNT approaches. TNT integrates chemotherapy and radiotherapy prior to surgery, potentially improving margin-negative resection rates and enabling curative resection for locally advanced cases. The lingering question: is more always better? This article categorizes TNT strategies into six main groups based on radiotherapy (RT) techniques: (1) conventional chemoradiotherapy (CRT), (2) the Dutch PREOPANC approach, (3) hypofractionated ablative intensity-modulated radiotherapy (HFA-IMRT), and stereotactic body radiotherapy (SBRT) techniques, which further divide into (4) non-ablative SBRT, (5) nearly ablative SBRT, and (6) adaptive ablative SBRT. A comprehensive analysis of the literature on TNT is provided for both borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), with detailed sections for each.

Purpose: Over the last decade, immune checkpoint inhibitors (ICI) have emerged as cornerstone in the treatment of many metastatic tumour types, including gastrointestinal cancers. In many solid tumours, the effective therapies in the metastatic field are progressively brought into the curative setting. Consequently, earlier tumoural settings have become a field of experiment for immunotherapies. In melanoma, lung, and bladder cancers, excellent results were recorded, possibly explained by differences in the tumour microenvironment between metastatic and non-metastatic settings. In gastrointestinal (GI) Oncology, nivolumab is the first immune checkpoint inhibitor to become a standard-of-care adjuvant treatment after curative surgery for oesophagal or gastroesophageal junction cancer. Recent findings: We herein discuss the results of a selection of the most relevant studies presented/published over the last 18 months testing immunotherapies in non-metastatic GI cancers. Among immunotherapies, ICI have been investigated in pre-, peri- and postoperative setting across tumour types, alone or in combination with chemo- and/or radiotherapy. Vaccines are also a new field of investigation. Summary: Promising results from two studies (NCT04165772 and NICHE-2 study) demonstrating never-seen-before responses to neoadjuvant immunotherapy in MMR deficient (dMMR) colorectal cancers raise hope for improving the patients’ outcome and developing organ-sparing strategies in this situation.

The fibroblast activation protein (FAP) has emerged as a compelling theranostic target because it is highly expressed in the tumour microenvironment of many solid malignancies, predominantly on cancer-associated fibroblasts and, in selected tumour types, also on tumour cells. Following the rapid clinical expansion of FAP-targeted PET imaging, FAP-targeted radionuclide therapy (FAP-TRT) is now being explored as a predominantly stromal-directed therapeutic strategy across a broad range of solid malignancies. However, unlike established theranostic paradigms, such as prostate-specific membrane antigen- and somatostatin receptor-directed radioligand therapies, FAP-TRT faces distinct biological and translational challenges, including stromal heterogeneity, variable patterns of FAP expression, and limited tumour retention of many early radioligands. This review outlines the biological rationale, mechanistic basis, radiopharmaceutical development, and emerging clinical evidence for FAP-TRT. We highlight the recent ligand-engineering strategies aimed to improve tumour residence time and absorbed dose, and to summarise the current clinical data with particular focus on dosimetry, safety, and early efficacy signals. We also discuss key future directions, including disease-focused clinical development and rational combination strategies with immune checkpoint inhibitors, DNA damage response inhibitors, and chemotherapy. Overall, the available data support the feasibility of FAP-TRT but also underscore the need for improved ligand design and biologically informed clinical development to define its role within the evolving theranostic landscape.

Circulating cytokines could be optimal biomarkers for prognostication and management decisions in colorectal cancer (CRC). Chemorefractory CRC patients with available plasma samples were included in this study. In the discovery cohort (n = 85), 182 circulating cytokines were tested with a semi-quantitative multiplex assay, and prognostic cytokines were analyzed in the validation cohort (n = 111) by ELISA. Overall survival (OS) was the primary outcome measure, with the false discovery rate (FDR) method (significance level of <0.01) being used to correct for multiple comparisons. Four cytokines were associated with OS in the discovery cohort: insulin-like growth factor-binding protein 1 (IGFBP-1) (HR 2.1 [95%CI: 1.58–2.79], FDR < 0.001), insulin-like growth factor-binding protein 2 (IGFBP-2) (HR 1.65 [95%CI: 1.28–2.13], FDR = 0.006), serum amyloid A (SAA) (HR 1.84 [95%CI: 1.39–2.43], FDR < 0.001), and angiotensin II (HR 1.65 [95%CI: 1.29–2.1], FDR = 0.006). Of these, IGFBP-1 (HR 2.70 [95%CI: 1.56–4.76], FDR = 0.007) and IGFBP-2 (HR 3.33 [95%CI: 1.64–6.67], FDR = 0.008) were confirmed to be independently associated with OS in the validation cohort. Patients with high concentrations of IGFBP-1 and/or IGFBP-2 had a median OS of 3.0 months as compared with 6.9 months for those with low concentrations of both cytokines (HR 2.44 [95%CI: 1.52–4.0], FDR = 0.002) Validation of circulating IGFBP-1 and IGFBP-2 as independent prognostic biomarkers for chemorefractory CRC in larger, independent series is warranted.