Impact on survival of sarcopenia, systemic inflammatory response and anthropometric factors after pancreatectomy for resectable pancreatic adenocarcinoma.

INTRODUCTION: Pancreatic adenocarcinoma (PDAC) is becoming a public health issue with a 5-years survival rate around 10%. Patients with PDAC are often sarcopenic, which impacts postoperative outcome. At the same time, overweight population is increasing and adipose tissue promotes tumor related-inflammation. With several studies supporting independently these data, we aimed to assess if they held an impact on survival when combined. METHODS: We included 232 patients from two university hospitals (CHU de Lille, Institut Paoli Calmette), from January 2011 to December 2018, who underwent Pancreaticoduodenectomy (PD) for resectable PDAC. Preoperative CT scan was used to measure sarcopenia and visceral fat according to international cut-offs. Neutrophil to lymphocyte (NLR) and platelet to lymphocyte ratios (PLR) were used to measure inflammation. For univariate and multivariate analyses, the Cox proportional-hazard model was used. P-values below 0.05 were considered significant. RESULTS: Sarcopenic patients with visceral obesity were less likely to survive than the others in multivariate analysis (OS, HR 1.65, p= 0.043). Cutaneous obesity did not influence survival. We also observed an influence on survival when we studied sarcopenia with visceral obesity (OS, p= 0.056; PFS, p = 0.014), sarcopenia with cutaneous obesity (PFS, p= 0.005) and sarcopenia with PLR (PFS, p= 0.043). This poor prognosis was also found in sarcopenic obese patients with high PLR (OS, p= 0.05; PFS, p= 0.01). CONCLUSION: Sarcopenic obesity was associated with poor prognosis after PD for PDAC, especially in patients with systemic inflammation. Pre operative management of these factors should be addressed in pancreatic cancer patients.

Use of Diagnostic Laparoscopy and Peritoneal Washings for Pancreatic Cancer.

Pancreatic adenocarcinoma is an aggressive malignancy that often presents with advanced disease. Accurate staging is essential for treatment planning and shared decision-making with patients. Staging laparoscopy is a minimally invasive procedure that can detect radiographically occult metastatic disease. Its routine use with the collection of peritoneal washings in patients with pancreatic cancer remains controversial. We, herein, review the current literature concerning staging laparoscopy and peritoneal washings in patients with pancreatic cancer.

Neoadjuvant and Adjuvant Therapy in Resectable Pancreatic Adenocarcinoma.

While pancreatic adenocarcinoma requires surgical resection definitive cure, treatment paradigms are shifting toward a neoadjuvant approach to systemic therapy. Rationale is twofold: micro-metastatic disease is likely present in a majority of patients, reinforcing the importance of systemic therapy regardless of resectability; moreover, systemic therapy is well-tolerated and improves surgical outcomes when delivered preoperatively. Second, a neoadjuvant approach allows for selection of biology and patients most likely to benefit from potentially morbid surgery. This review examines the increasing body of evidence in support of empiric neoadjuvant therapy in pancreatic adenocarcinoma.

Prognostic and diagnostic value of circulating IGFBP2 in pancreatic cancer.

Insulin-like growth factor binding protein 2 (IGFBP2) is overexpressed in tumor tissues of several malignancies, including pancreatic cancer. Because of its role in tumor progression, IGFBP2 has been investigated as a tumor biomarker. However, little is known about its utility in pancreatic cancer. Plasma IGFBP2 levels were determined using enzyme-linked immunosorbent assay in 75 patients with pancreatic ductal adenocarcinoma (PDAC), 73 matched healthy controls, and 17 chronic pancreatitis patients. Our results showed that the plasma IGFPB2 level was significantly higher in PDAC patients than in patients with chronic pancreatitis and healthy controls. At a cut-off value of 333.9 ng/mL, the specificity and sensitivity were 78.08 and 65.33%, respectively. IGFBP2 level alone did not outperform carbohydrate antigen 19-9 (CA19-9) in diagnostic accuracy, but it successfully identified 9 out of 24 PDAC patients who were misidentified by CA19-9. The combination of IGFBP2 and CA19-9 was more accurate in the detection of PDAC than CA19-9 alone. IGFBP2 was more accurate than the other in discriminating between chronic pancreatitis and PDAC. Plasma IGFBP2, rather than CA19-9, was higher in the new-onset diabetes, lymph node involvement, and distant metastasis subgroups. IGFBP2 level was notably higher in stage IV cases than in stage I/II or stage III disease. However, CA19-9 did not show a difference between stages. After adjusting for lymph node involvement and distant metastasis, plasma IGFBP2 was identified as an independent prognostic marker for PDAC. The median survival time for patients with an IGFBP2 level ≥333.9 ng/mL was significantly shorter than that for patients with an IGFBP2 level <333.9 ng/mL. Marked elevation of plasma IGFBP2 in PDAC is associated with poorer survival. IGFBP2 may be considered as a supplementary biomarker for the diagnosis and prognostic prediction in Chinese pancreatic cancer patients.

Pancreatitis, panniculitis, and polyarthritis syndrome in a dog with hyalinizing pancreatic adenocarcinoma.

A 10-y-old spayed female Cavalier King Charles Spaniel dog was presented to the Veterinary Teaching Hospital because of recurrent chronic abscesses on the distal pelvic limbs, fever, lethargy, lameness of unknown etiology, and chronic pancreatitis. Sterile nodular panniculitis was diagnosed after an extensive workup, and the dog initially responded to immunosuppressive therapy, but relapse and spread of cutaneous lesions and acute lameness occurred after 11 mo, and euthanasia was elected. Postmortem examination confirmed hyalinizing pancreatic adenocarcinoma with pancreatitis, panniculitis, polyarthritis (PPP), and osteomyelitis. Histopathology and bacterial and fungal cultures were supportive of a sterile process, specifically the PPP syndrome, which is a rare, potentially life-threatening, systemic manifestation of pancreatic disease in both people and animals. To our knowledge, a clinicopathologic description of a hyalinizing pancreatic adenocarcinoma associated with this rare syndrome has not been reported previously in a dog.

Metastatic Pancreatic Adenocarcinoma Downstaged to T0N0 with Chemotherapy and Targeted Therapy, Confirmed by Surgical Pathology: A Case Report.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive human tumor that is typically diagnosed at a later stage when surgery is not possible. Case Presentation: We report the case of a 62-year-old woman who presented to the emergency department with abdominal pain. Computed tomography (CT) revealed a solitary hepatic lesion and a pancreatic body lesion. The pancreatic body lesion was biopsied endoscopically, and a tissue diagnosis was obtained to confirm the diagnosis of PDAC. She was then treated with 12 cycles of FOLFIRINOX with stable disease on CT. Due to the history of a hepatic lesion, she received 11 cycles of gemcitabine/Abraxane and a combination of a MEK inhibitor, Mekinist, and a BRAF inhibitor, BRAFTOVI. Subsequently, the patient underwent a liver biopsy. The biopsy result was negative, and the tumor was deemed resectable. The patient underwent a distal pancreatectomy. Surgical pathology demonstrated a 1.1-cm low-grade papillary mucinous neoplasm with negative margins and lymph nodes, staged T0N0. Adjuvant chemotherapy was not administered. Conclusion: To our knowledge, this is the first report of a patient with metastatic pancreatic adenocarcinoma who received prolonged IV and oral chemotherapy. At the time of the operation, the pathological stage was T0N0. The patient has recently been seen 9 months after surgery with no evidence cancer recurrence. Additionally, ctDNA remains negative.

Clinical and molecular features of early onset pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is a major health burden and may become the second cause of death by cancer in developed countries. The incidence of early-onset pancreatic cancer (EOPC, defined by an age at diagnosis <50 years old) is increasing. Here, we conducted a study of all PDAC patients followed at our institution. Patients were classified as EOPC or non-early onset (nEOPC, >50). Eight hundred and seventy eight patients were included, of which 113 EOPC, exhibiting a comparable performance status. EOPC were more often diagnosed at the metastatic stage (70.0% vs 58.3%) and liver metastases were more prevalent at diagnosis (60.2% vs. 43.9%). The median overall survival (OS) from diagnosis was 18.1 months, similar between EOPC and nEOPC. Among patients who underwent surgery, recurrence-free survival was similar between age groups. Among metastatic patients, first line progression free survival was similar but EOPC received more treatment lines (72.3% vs. 58.1% received ≥2 lines). Regarding molecular alterations, the mean tumor mutational burden (TMB) was lower in EOPC (1.42 vs. 2.95 mut/Mb). The prevalence of KRAS and BRCA1/2 mutations was similar, but EOPC displayed fewer alterations in CNKN2A/B. Fifty eight patients (18.6%) had actionable alterations (ESCAT I-III) and 31 of them received molecularly matched treatments. On the transcriptomic level, despite its clinical aggressiveness, EOPC was less likely to display a basal-like phenotype. To conclude, EOPC were diagnosed more frequently at the metastatic stage. OS and 1st line PFS were similar to nEOPC. EOPC displayed specific molecular features, such as a lower TMB and fewer alterations in CDKN2A/B.

TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function.

Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.

Investigating underlying molecular mechanisms, signaling pathways, emerging therapeutic approaches in pancreatic cancer.

Pancreatic adenocarcinoma, a clinically challenging malignancy constitutes a significant contributor to cancer-related mortality, characterized by an inherently poor prognosis. This review aims to provide a comprehensive understanding of pancreatic adenocarcinoma by examining its multifaceted etiologies, including genetic mutations and environmental factors. The review explains the complex molecular mechanisms underlying its pathogenesis and summarizes current therapeutic strategies, including surgery, chemotherapy, and emerging modalities such as immunotherapy. Critical molecular pathways driving pancreatic cancer development, including KRAS, Notch, and Hedgehog, are discussed. Current therapeutic strategies, including surgery, chemotherapy, and radiation, are discussed, with an emphasis on their limitations, particularly in terms of postoperative relapse. Promising research areas, including liquid biopsies, personalized medicine, and gene editing, are explored, demonstrating the significant potential for enhancing diagnosis and treatment. While immunotherapy presents promising prospects, it faces challenges related to immune evasion mechanisms. Emerging research directions, encompassing liquid biopsies, personalized medicine, CRISPR/Cas9 genome editing, and computational intelligence applications, hold promise for refining diagnostic approaches and therapeutic interventions. By integrating insights from genetic, molecular, and clinical research, innovative strategies that improve patient outcomes can be developed. Ongoing research in these emerging fields holds significant promise for advancing the diagnosis and treatment of this formidable malignancy.

Antibody-drug conjugates for hepato-pancreato-biliary malignancies: "Magic bullets" to the rescue?

Hepato-Pancreato-Biliary (HPB) malignancies constitute a highly aggressive group of cancers that have a dismal prognosis. Patients not amenable to curative intent surgical resection are managed with systemic chemotherapy which, however, confers little survival benefit. Antibody-Drug Conjugates (ADCs) are tripartite compounds that merge the intricate selectivity and specificity of monoclonal antibodies with the cytodestructive potency of attached supertoxic payloads. In view of the unmet need for drugs that will enhance the survival rates of HPB cancer patients, the assessment of ADCs for treating HPB malignancies has become the focus of extensive clinical and preclinical investigation, showing encouraging preliminary results. In the current review, we offer a comprehensive overview of the growing body of evidence on ADC approaches tested for HPB malignancies. Starting from a concise discussion of the functional principles of ADCs, we summarize here all available data from preclinical and clinical studies evaluating ADCs in HPB cancers.

Chemotherapy switch for nonresponse or progression on neoadjuvant chemotherapy for pancreatic adenocarcinoma.

BACKGROUND AND OBJECTIVES: Patients with localized pancreatic adenocarcinoma who do not respond to neoadjuvant therapy present a challenge. We sought to define the characteristics and outcomes of those patients to guide clinical practice. METHODS: Patients included were those without evidence of biochemical or radiographic response and no evidence of distant progression at the first reassessment after initiation of therapy. RESULTS: Of the 45 patients in the cohort, 23 (51.1%) proceeded to surgical exploration with all but one of those undergoing resection. The median overall survival of the study cohort was 28.6 and 48.6 months in those who underwent resection. A total of 13 patients (28.9%) underwent chemotherapy switch (CS) during their course of neoadjuvant therapy. The CS cohort demonstrated higher rates of radiologic progression (25% vs. 10%, p = 0.329), new or worse vascular involvement (58.3% vs. 30%, p = 0.082), and CA 19-9 increase (30.8% vs. 12.9%, p = 0.209) at initial re-staging. Despite this, overall survival was similar between the two groups (20.7 vs. 28.7 months, p = 0.674). CONCLUSION: Non-responders to first-line neoadjuvant therapy have poor rates of curative-intent resection. However, resection should be undertaken when feasible. CS may be considered in patients who do not respond to first-line chemotherapy.

Insights into gemcitabine resistance in pancreatic cancer: association with metabolic reprogramming and TP53 pathogenicity in patient derived xenografts.

BACKGROUND: With poor prognosis and high mortality, pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Standard of care therapies for PDAC have included gemcitabine for the past three decades, although resistance often develops within weeks of chemotherapy initiation through an array of possible mechanisms. METHODS: We reanalyzed publicly available RNA-seq gene expression profiles of 28 PDAC patient-derived xenograft (PDX) models before and after a 21-day gemcitabine treatment using our validated analysis pipeline to identify molecular markers of intrinsic and acquired resistance. RESULTS: Using normalized RNA-seq quantification measurements, we first identified oxidative phosphorylation and interferon alpha pathways as the two most enriched cancer hallmark gene sets in the baseline gene expression profile associated with intrinsic gemcitabine resistance and sensitivity, respectively. Furthermore, we discovered strong correlations between drug-induced expression changes in glycolysis and oxidative phosphorylation genes and response to gemcitabine, which suggests that these pathways may be associated with acquired gemcitabine resistance mechanisms. Thus, we developed prediction models using baseline gene expression profiles in those pathways and validated them in another dataset of 12 PDAC models from Novartis. We also developed prediction models based on drug-induced expression changes in genes from the Molecular Signatures Database (MSigDB)'s curated 50 cancer hallmark gene sets. Finally, pathogenic TP53 mutations correlated with treatment resistance. CONCLUSION: Our results demonstrate that concurrent upregulation of both glycolysis and oxidative phosphorylation pathways occurs in vivo in PDAC PDXs following gemcitabine treatment and that pathogenic TP53 status had association with gemcitabine resistance in these models. Our findings may elucidate the molecular basis for gemcitabine resistance and provide insights for effective drug combination in PDAC chemotherapy.

68Ga-labeled fibroblast activation protein inhibitor (FAPI) PET/CT for locally advanced or recurrent pancreatic cancer staging and restaging after chemoradiotherapy.

Purpose: 68Ga-labeled fibroblast activation protein inhibitor (FAPI) is a novel PET tracer with great potential for staging pancreatic cancer. Data on locally advanced or recurrent disease is sparse, especially on tracer uptake before and after high dose chemoradiotherapy (CRT). The aim of this study was to evaluate [68Ga]Ga-FAPI-46 PET/CT staging in this setting. Methods: Twenty-seven patients with locally recurrent or locally advanced pancreatic adenocarcinoma (LRPAC n = 15, LAPAC n = 12) in stable disease or partial remission after chemotherapy underwent FAPI PET/CT and received consolidation CRT in stage M0 with follow-up FAPI PET/CT every three months until systemic progression. Quantitative PET parameters SUVmax, SUVmean, FAPI-derived tumor volume and total lesion FAPI-uptake were measured in baseline and follow-up PET/CT scans. Contrast-enhanced CT (ceCT) and PET/CT data were evaluated blinded and staged according to TNM classification. Results: FAPI PET/CT modified staging compared to ceCT alone in 23 of 27 patients in baseline, resulting in major treatment alterations in 52% of all patients (30%: target volume adjustment due to N downstaging, 15%: switch to palliative systemic chemotherapy only due to diffuse metastases, 7%: abortion of radiotherapy due to other reasons). Regarding follow-up scans, major treatment alterations after performing FAPI PET/CT were noted in eleven of 24 follow-up scans (46%) with switch to systemic chemotherapy or best supportive care due to M upstaging and ablative radiotherapy of distant lymph node and oligometastasis. Unexpectedly, in more than 90 % of the follow-up scans, radiotherapy did not induce local fibrosis related FAPI uptake. During the first follow-up, all quantitative PET metrics decreased, and irradiated lesions showed significantly lower FAPI uptake in locally controlled disease (SUVmax p = 0.047, SUVmean p = 0.0092) compared to local failure. Conclusion: Compared to ceCT, FAPI PET/CT led to major therapeutic alterations in patients with LRPAC and LAPAC prior to and after radiotherapy, which might help identify patients benefiting from adjustments in every treatment stage. FAPI PET/CT should be considered a useful diagnostic tool in LRPAC or LAPAC before and after CRT.

Quantitative Edge Analysis Can Differentiate Pancreatic Carcinoma from Normal Pancreatic Parenchyma.

This study aimed to introduce specific image feature analysis, focusing on pancreatic margins, and to provide a quantitative measure of edge irregularity, evidencing correlations with the presence/absence of pancreatic adenocarcinoma. We selected 50 patients (36 men, 14 women; mean age 63.7 years) who underwent Multi-detector computed tomography (MDCT) for the staging of pancreatic adenocarcinoma of the tail of the pancreas. Computer-assisted quantitative edge analysis was performed on the border fragments in MDCT images of neoplastic and healthy glandular parenchyma, from which we obtained the root mean square deviation SD of the actual border from the average boundary line. The SD values relative to healthy and neoplastic borders were compared using a paired t-test. A significant SD difference was observed between healthy and neoplastic borders. A threshold SD value was also found, enabling the differentiation of adenocarcinoma with 96% specificity and sensitivity. We introduced a quantitative measure of boundary irregularity, which correlates with the presence/absence of pancreatic adenocarcinoma. Quantitative edge analysis can be promptly performed on select border fragments in MDCT images, providing a useful supporting tool for diagnostics and a possible starting point for machine learning recognition based on lower-dimensional feature space.

Comprehensive exploration of immune checkpoint-related genes in the prognosis and tumor immune microenvironment of pancreatic adenocarcinoma.

BACKGROUND: To comprehensively analyze the clinical significance of Immune Checkpoint-Related Genes (ICRGs) in Pancreatic Adenocarcinoma (PAAD). METHOD: PAAD tissues and normal pancreatic tissues were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, and 283 ICRGs were integrated by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome datasets. Unsupervised clustering was used to obtain potential ICRGs-based PAAD subtypes. Wilcoxon test was performed to screen Differentially Expressed ICRGs (DEICRGs), while cox regression analyses were utilized to identify prognosis-related ICRGs and clinicopathological factors, and construct the corresponding models. The Tumor Immune Microenvironment (TIME) was evaluated. Moreover, the authors performed enrichment analysis, Gene Set Enrichment Analysis (GSEA), and transcription factor regulatory networks to realize underlying mechanisms. RESULTS: Three ICRGs-based PAAD subtypes were identified, and they were associated with three ESTIMATE scores, a Tumor Microenvironment (TMB) score, 14 therapeutic immune checkpoints, and infiltration levels of seven immune cells. On top of that, the authors constructed two signatures based on DEICRGs to predict the Overall Survival (OS) (Area Under the ROC Curve [AUC: 0.741∼0.778]) and Progression-Free Survival (PFS) (AUC: 0.746∼0.831) of patients. Two nomograms were established by combining clinical variables and signatures. In addition, the authors found higher infiltration of naïve B cells and CD8+ T-cells in low-risk PAAD patients, and higher infiltration of suppressive immune cells and cancer-related signaling pathways in high-risk PAAD patients. CONCLUSION: The present study suggested that ICRGs were associated with TIME formation and prognosis of PAAD patients, which may serve as novel clinical biomarkers and therapeutic targets.

A prognostic biomarker of disulfidptosis constructed by machine learning framework model as potential reporters of pancreatic adenocarcinoma.

BACKGROUND: Pancreatic adenocarcinoma (PAAD), known for its high lethality, has not been thoroughly explored in terms of its mechanisms and patterns of immune infiltration. Disulfidptosis, a newly identified mode of cell death, is likely associated with tumorigenesis and progression but remains poorly understood in PAAD at the genetic and mechanistic levels. METHODS: Sixteen PAAD samples from the GSE154778 scRNA-seq dataset were subjected to single-cell analysis. Disulfidptosis grouping and scores were established across various immune cell populations. Using the TCGA-PAAD database, LASSO regression was employed to construct prognostic markers linked to disulfidptosis. The performance of this model was assessed in both training and independent validation cohorts. Subsequent analyses explored the correlations between disulfidptosis scores, immune infiltration, and drug sensitivity. Cellular experiments further confirmed the significant positive relationship of the gene MET with disulfidptosis and its role in influencing the invasion and metastasis of PAAD. RESULTS: WGCNA identified Disulf-High and Disulf-Low as modules strongly correlated with disulfidptosis. Five prognostically significant genes were selected to construct prognostic models. Survival analysis demonstrated that the disulfidptosis-related biological model successfully achieved prognostic stratification in PAAD patients. Additionally, the disulfidptosis score was significantly correlated with both immune infiltration and drug sensitivity. Knockdown of the MET gene substantially inhibited cell multiplication and cell cycle progression in two PAAD cell lines, effects potentially induced by the activation of the PI3K/AKT signalling pathway in the tumour. CONCLUSION: Key genes associated with disulfidptosis significantly correlate with immune infiltration and the development of PAAD. Biomarkers based on disulfidptosis present potential avenues for novel therapies and clinical treatments in PAAD.

Leveraging real-world data to predict cancer cachexia stage, quality of life, and survival in a racially and ethnically diverse multi-institutional cohort of treatment-naïve patients with pancreatic ductal adenocarcinoma.

Introduction: Cancer-associated cachexia (CC) is a progressive syndrome characterized by unintentional weight loss, muscle atrophy, fatigue, and poor outcomes that affects most patients with pancreatic ductal adenocarcinoma (PDAC). The ability to identify and classify CC stage along its continuum early in the disease process is challenging but critical for management. Objectives: The main objective of this study was to determine the prevalence of CC stage overall and by sex and race and ethnicity among treatment-naïve PDAC cases using clinical, nutritional, and functional criteria. Secondary objectives included identifying the prevalence and predictors of higher symptom burden, supportive care needs, and quality of life (QoL), and examining their influence on overall survival (OS). Materials and methods: A population-based multi-institutional prospective cohort study of patients with PDAC was conducted between 2018 and 2021 by the Florida Pancreas Collaborative. Leveraging patient-reported data and laboratory values, participants were classified at baseline into four stages [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca), and refractory cachexia (RCa)]. Multivariate regression, Kaplan Meier analyses, and Cox regression were conducted to evaluate associations. Results: CC stage was estimated for 309 PDAC cases (156 females, 153 males). The overall prevalence of NCa, PCa, Ca, and RCa was 12.9%, 24.6%, 54.1%, and 8.4%, respectively. CC prevalence across all CC stages was highest for males and racial and ethnic minorities. Criteria differentiated NCa cases from other groups, but did not distinguish PCa from Ca. The most frequently reported symptoms included weight loss, fatigue, pain, anxiety, and depression, with pain significantly worsening over time. The greatest supportive care needs included emotional and physical domains. Males, Black people, and those with RCa had the worst OS. Conclusions: Using clinical, nutritional, and functional criteria, nearly one-quarter of the PDAC cases in our diverse, multi-institutional cohort had PCa and 62.5% had Ca or RCa at the time of diagnosis. The PCa estimate is higher than that reported in prior studies. We recommend these criteria be used to aid in CC classification, monitoring, and management of all incident PDAC cases. Findings also highlight the recommendation for continued emotional support, assistance in alleviating pain, and supportive care needs throughout the PDAC treatment journey.

PanIN and CAF transitions in pancreatic carcinogenesis revealed with spatial data integration.

This study introduces a new imaging, spatial transcriptomics (ST), and single-cell RNA-sequencing integration pipeline to characterize neoplastic cell state transitions during tumorigenesis. We applied a semi-supervised analysis pipeline to examine premalignant pancreatic intraepithelial neoplasias (PanINs) that can develop into pancreatic ductal adenocarcinoma (PDAC). Their strict diagnosis on formalin-fixed and paraffin-embedded (FFPE) samples limited the single-cell characterization of human PanINs within their microenvironment. We leverage whole transcriptome FFPE ST to enable the study of a rare cohort of matched low-grade (LG) and high-grade (HG) PanIN lesions to track progression and map cellular phenotypes relative to single-cell PDAC datasets. We demonstrate that cancer-associated fibroblasts (CAFs), including antigen-presenting CAFs, are located close to PanINs. We further observed a transition from CAF-related inflammatory signaling to cellular proliferation during PanIN progression. We validate these findings with single-cell high-dimensional imaging proteomics and transcriptomics technologies. Altogether, our semi-supervised learning framework for spatial multi-omics has broad applicability across cancer types to decipher the spatiotemporal dynamics of carcinogenesis.

Driver mutation subtypes involve with differentiated immunophenotypes influencing pancreatic cancer outcomes.

Despite many studies focusing on the prognostic biomarkers in pancreatic adenocarcinomas (PAADs), there is ill-informed about the relationships between their genomic features and immune characteristics. Herein, we deeply investigated the involvement of major driver mutation subtypes with immunophenotypes impacting PAAD outcomes. Based on public data analyses of RNA expression-based immune subtypes in PAAD, in contrast to KRAS G12D & TP53 co-mutant patients with poor outcomes, the best immune subtype C3 (inflammatory) characterized by high Th1/Th2 ratio was relatively enriched in KRASnon-G12DTP53wt patients with better survival, whereas the inferior subtype C2 (IFN-γ dominant) with low Th1/Th2 ratio was more common in the former than in the latter. Moreover, contrary to the highly immunosuppressive microenvironment (high Treg, high ratio of Treg to tumor-specific CD4+ T cell) in KRASG12DTP53mut patients, KRASG12VTP53wt individuals exhibited an inflamed context profiled by multiplex immunohistochemistry. It could be responsible for their outstanding survival advantage over others in postsurgical PAAD patients receiving adjuvant chemotherapy as shown by our cohort. Together, KRASG12VTP53wt may be a promising biomarker for prognostic evaluation and screening certain candidates with PAAD to get desirable survival benefit from adjuvant chemotherapy.