Tumor size (TS) in pancreatic ductal adenocarcinoma (PDAC) is one of the most important prognostic factors. However, discrepancies between TS on preoperative images (TSi) and pathological specimens (TSp) have been reported. This study aims to evaluate the factors associated with the differences between TSi and TSp.

We retrospectively analyzed patients with PDAC who underwent surgery at our institution between January 2010 and November 2023. TS discrepancy (TSD[%]) was defined as ([TSp - TSi]/TSp) × 100. Using logistic regression, we generated a receiver operating characteristic (ROC) curve to define the cutoff for TSi underestimation predicting clinical tumor (T) stage migration. Univariate and multivariate analyses were performed to evaluate predictors of TSi underestimation.

Of the 231 patients, 99 (42%) patients received preoperative chemotherapy. The ROC curve determined a TSD underestimation cutoff of 25.9%. The number of TSp > TSi cases was 185 (80%), and TSi underestimation was present in 117 (51%) patients. T stage migration rates were 76%, 26%, and 50% in clinical stage (c) T1, cT2, cT3, respectively, among the patients with chemotherapy, and 93%, 33%, and 14%, respectively, in those without chemotherapy. Multivariate analyses revealed that independent predictors of TSi underestimation were posterior surface invasion in the patients with preoperative chemotherapy and anterior surface invasion in those without chemotherapy.

TS was more commonly underestimated than overestimated, and cT1 rarely corresponded to pathological (p)T1. The factors contributing to TSi underestimation differed between patients with and without preoperative chemotherapy. Therefore, these two groups should be considered separately for accurate TSi evaluation.

The efficacy of neoadjuvant chemoradiotherapy for resectable pancreatic ductal adenocarcinoma (R-PDAC) remains unclear. This study was designed to evaluate neoadjuvant chemoradiotherapy by using intensity-modulated radiotherapy (NAC-IMRT) for R-PDAC compared with upfront surgery (UpS).

Among 198 patients with R-PDAC who were indicated for resection between 2013 and 2021, 130 were included in this study after excluding patients who underwent neoadjuvant chemotherapy and did not meet the NAC-IMRT criteria (Eligible set). NAC-IMRT was planned for 58 patients, and UpS was planned for 72 patients. Additionally, in 105 patients who could undergo the planned treatment (As-treated set), the surgical, pathological, and oncological outcomes were evaluated.

In the Eligible set, median overall survival (OS) was 50.5 months with NAC-IMRT and 34.7 months with UpS and progression-free survival was 20.4 months with NAC-IMRT and 13.9 months with UpS. In the As-treated set, OS was longer in the NAC-IMRT group (66.7 months vs. 34.7 months, p = 0.007). On multivariate analysis, NAC-IMRT was identified as an independent factor for better OS (hazard ratio 0.617, 95% confidence interval 0.382-0.995, p = 0.047, in the Eligible set). The incidence of postoperative complications did not show a difference between the two groups, and NAC-IMRT suppressed local tumor invasion, including lymphatic, venous, perineural invasion, and lymph node metastases.

NAC-IMRT may offer superior survival outcomes and manageable toxicity in R-PDAC patients compared with upfront surgery. This study supports the efficacy and safety of NAC-IMRT and recommends its consideration in R-PDAC treatment protocols.

Liposomal irinotecan + fluorouracil/leucovorin (nal-IRI + 5FU/LV) is commonly used as a second- or later-line treatment for pancreatic ductal adenocarcinoma (PDAC) and offers survival benefits. However, its efficacy and safety in patients previously treated with FOLFIRINOX, which includes irinotecan, remain unclear. We evaluated the efficacy and safety of nal-IRI + 5FU/LV in patients with unresectable PDAC who received previous FOLFIRINOX therapy and those who did not.

This retrospective observational study included 42 patients with PDAC who were treated with nal-IRI + 5FU/LV (October 2020-November 2023). Patients were grouped based on prior FOLFIRINOX treatment.

The progression-free survival (PFS) in patients who previously received modified FOLFIRINOX (mFFX) therapy was shorter than that in patients who did not (2.5 vs. 3.5 months, P = 0.07). When patients with greater than- and less than the cut-off value of irinotecan-free interval (IFI) were classified into the long and short IFI groups, respectively, PFS was significantly longer in the long-IFI group than that in the short IFI group (4.0 vs. 2.1 months, P = 0.01). Moreover, the C-reactive protein/albumin ratio (CAR) was also a significant predictor of PFS (P = 0.03). Furthermore, both factors were found to be independent factors influencing PFS in the univariate Cox regression analysis (P = 0.02 and P = 0.04).

Nal-IRI + 5FU/LV therapy may be a safe and effective option as a second- or later-line treatment, particularly for patients who have not previously received mFFX therapy. For patients who received prior mFFX exposure, a longer IFI and lower CAR may indicate greater potential benefit, thus aiding in more personalized treatment approaches.

Liposomal irinotecan (nal-IRI) plus fluorouracil/folinic acid (5-FU/LV) improves survival in gemcitabine-refractory metastatic pancreatic cancer (PC) but requires a central venous port. S-1, an oral fluoropyrimidine with proven efficacy in PC, may replace 5-FU/LV in nal-IRI plus 5-FU/LV, potentially enhancing both convenience and antitumor effect.

This single-arm, open-label, phase 1/2 study included patients with histologically or cytologically confirmed adenocarcinoma, aged 20-80 years, an Eastern Cooperative Oncology Group performance status of 0-1, with metastatic disease, and refractory to gemcitabine-based treatment. The primary endpoint in phase 1 part was the frequency of dose-limiting toxicity (DLT) to nal-IRI plus S-1. The primary endpoint in phase 2 part was overall survival. This trial was registered in the Japan Registry of Clinical Trials database (jRCTs031210040).

In phase 1 part, one patient with DLT was observed at nal-IRI 70 mg/m2 (day 1) with S-1 80 mg/m2/day (day 1-7) in a 2-week cycle, establishing this as the recommended phase 2 dose (RP2D). Forty-nine patients from phase 1 (n = 6) and phase 2 part (n = 43) were treated with the RP2D, and their results were pooled. Median overall survival was 10.3 months (95 % confidence interval, 8.1-12.0 months). A confirmed partial response was achieved in 10 patients (20.4 %). The most frequent treatment-emergent adverse events were hypoalbuminemia (98.0 %), anemia (98.0 %), and anorexia (81.6 %). There were no treatment-related deaths.

This study demonstrated that nal-IRI plus S-1 exhibited promising efficacy and an acceptable safety profile in patients with metastatic PC refractory to gemcitabine-based treatment.

Histopathological stage I pancreatic cancer (PC) consists of four entities according to the Union for International Cancer Control (UICC) 8th staging system: pStage IA (cases underwent up-front surgery, pT1 [tumor size ≤20 mm] pN0), pStage IB (cases underwent up-front surgery, pT2 [20 mm < tumor size ≤40 mm] pN0), ypStage IA and IB (i.e., underwent neoadjuvant treatment [NAT]). This study aimed to evaluate surgical outcomes in patients with histopathological stage I PC ((y)pStage I).

Patients with PC who underwent resection and were diagnosed with (y)pStage I were included in this study (n = 121). We evaluated and compared recurrence-free survival (RFS) and overall survival (OS) among these four categories: pStage I vs. ypStage I, (y)pStage IA vs. IB, ypStage IA vs. IB, and pStage IA vs. IB.

There was no difference in the prognosis between pStage I and ypStage I cases, even though ypStage I included more advanced cases at NAT initiation. For pStage I (n = 25), no differences in prognosis were noted between pStage IA and IB (median RFS, 24 vs. 21 months, p = 0.871; median OS, 49.5 vs. 35.5 months, p = 0.213). However, in the ypStage I cohort (n = 96), there was significantly better RFS in ypStage IA (median RFS, 42 vs. 14 months, p = 0.0114; median OS, 52 vs. 36 months, p = 0.250).

Survival was comparable between pStage I and ypStage I cohorts, although the subcategories within each cohort (IA vs. IB) had different clinicopathological characteristics and outcomes.

Surgical resection of pancreatic ductal adenocarcinoma (PDAC) modestly improves long-term survival due to the competing risk of metastatic disease. However, postoperative morbidity often interferes with administration of systemic therapy and may be unacceptable to some patients. Ablative radiation therapy (A-RT) has emerged as an effective noninvasive local treatment in many tumor types and may provide an alternative to surgery in select patients with resectable PDAC.

To estimate the efficacy of A-RT in technically resectable PDAC.

This cohort study of consecutive patients with histologically confirmed, radiographically resectable T1-2N0-1M0 PDAC treated with A-RT at Memorial Sloan Kettering Cancer Center between June 2016 and December 2022 were included from a prospectively maintained database. Patients were not eligible for surgery because of noncancer-related comorbidities. Data were frozen for analysis in December 2023, which took place between March and November 2024.

All patients received A-RT exceeding 97.5-Gy biologically effective dose with daily computed tomography or magnetic resonance imaging guidance, motion management, and daily or selective adaptation of the dose distribution.

The primary outcome was overall survival (OS). Secondary outcomes included biochemical and radiographic objective response rate, cumulative incidence of local progression, progression-free survival, and distant metastasis-free survival.

Of 25 patients with radiographically resectable PDAC who received A-RT, 13 (52%) were male, and the median (IQR) age at time of A-RT was 80 (74-87) years. A total of 20 patients (80%) had a Karnofsky Performance Status score of 80 or lower. A total of 15 tumors (60%) were T2, and 4 (16%) were node positive. A total of 17 patients (68%) received induction chemotherapy for a median (range) of 2.9 (1.0-6.1) months. Radiation therapy regimens delivered with conventional linear accelerators included 75 Gy in 25 fractions among 13 patients, 67.5 Gy in 15 fractions among 9 patients, 50 Gy in 5 fractions among 2 patients (magnetic resonance imaging-guided linear accelerator), and 60 Gy in 10 for 1 patient. OS, local progression, and distant metastasis-free survival at 2 years were 43.7% (95% CI, 27.4%-69.5%), 20.8% (95% CI, 7.3%-39.0%), and 20.0% (95% CI, 9.1%-43.8%), respectively. Grade 3 acute and late gastrointestinal tract toxic effects were noted in 3 and 1 patients, respectively, with no grade 4 or higher events.

In this cohort study, A-RT in patients with technically resectable PDAC led to effective local tumor control and favorable OS despite advanced age, poor Karnofsky Performance Status score, and conservative use of chemotherapy in the cohort studied. These data support a prospective study of A-RT for the management of resectable PDAC.

Pancreatic cancer is frequently a lethal disease with an aggressive tumour biology often presenting with non-specific symptoms. Median survival is approximately 4 months with a 5-year survival of 13%. Surveillance is recommended in individuals with familial pancreatic cancer, specific mutations, and high-risk intraductal papillary mucinous neoplasm, as they are at high risk of developing pancreatic cancer. Chemotherapy combined with surgical resection remains the cornerstone of treatment. However, only a small subset of patients are candidates for surgery. Multi-agent chemotherapy has improved survival in the palliative setting for patients with metastatic disease, as (neo)adjuvant and induction therapy have in patients with borderline resectable and locally advanced pancreatic. Given that pancreatic cancer is predicted to become the second leading cause of cancer-related death by 2030, novel therapies are urgently needed.

Pancreatic cancer shows very poor prognosis and high resistance to conventional standard chemotherapy and immunotherapy; therefore, the development of new breakthrough therapies is highly desirable.

We retrospectively evaluated the safety and efficacy of neoantigen peptide-pulsed dendritic cell (Neo-P DC) vaccine therapy after surgical treatment of pancreatic cancer.

The result showed induction of neoantigen-specific T cells in 13 (81.3%) of the 16 patients who received Neo-P DC vaccines. In survival analysis of the nine patients who received Neo-P DC vaccines after recurrence, longer overall survival was observed in patients with neoantigen-specific T cell induction than those without T cell induction. Notably, only one of the seven patients who received Neo-P DC vaccines as adjuvant setting developed recurrence, and no patient died during median follow-up 61 months after surgery (range, 25-70 months). Furthermore, TCR repertoire analyses were performed in a case treated with Neo-P DC vaccine combined with long and short peptides, and one significantly dominant clone induced by the long peptide was detected among CD4+ T cell populations.

The present study suggests the feasibility and efficacy of Neo-P DC vaccine therapy after surgical treatment of pancreatic cancer in both postoperative recurrence cases and adjuvant setting. A case analysis suggests the importance of combination with long peptides targeting CD4+ T cell.

Pancreatic ductal adenocarcinoma (PDAC) has a very poor prognosis and high mortality. The prognosis for recurrence after surgery is extremely poor. Resection for disseminations of PDAC is not recommended.

The patient was a 69-year-old woman with a pancreatic tumor that was detected with computed tomography (CT) during a postoperative colon cancer checkup. She was suspected of having pancreatic body cancer without distant metastasis. Distal pancreatectomy with celiac axis resection was performed. Postoperative pathological examination revealed an invasive ductal adenocarcinoma with lymph node metastasis (pT4N1M0, stage III). Postoperatively, she received adjuvant chemotherapy containing gemcitabine and S-1 for 1 year and 4 months, and S-1 monotherapy for 1 year. Six years and 2 months after the initial surgery, her serum carbohydrate antigen 19-9 level elevated, and CT revealed soft tissue in front of the left kidney. Positron emission tomography/CT also revealed high fluorine-18 fluorodeoxyglucose uptake in the tissue. Accordingly, the patient was diagnosed with dissemination of PDAC. The patient was administered chemotherapy with gemcitabine and S-1. One year and 6 months after the diagnosis of dissemination, CT revealed reduction of the nodule. Therefore, we decided to eliminate this dissemination. A left nephrectomy and partial gastrectomy were performed. Histopathological examination confirmed dissemination of PDAC. The patient refused adjuvant chemotherapy. No evidence of recurrence has been observed for 13 years and 3 months since the initial surgery, and 5 years and 1 month since the resection of the dissemination.

This case showed a recurrence of dissemination after radical PDAC surgery, and the patient showed long-term survival without recurrence after dissemination resection. Resection of dissemination may confer long-term survival in selected patients.

Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, aggressive progression, and resistance to conventional therapies. Despite advances in understanding its pathogenesis, including the identification of common genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) and dysregulated signaling pathways (e.g., KRAS-MAPK, PI3K-AKT, and TGF-β pathways), effective therapeutic strategies remain limited. Current treatment modalities including chemotherapy, targeted therapy, immunotherapy, radiotherapy, and emerging therapies such as antibody-drug conjugates (ADCs), chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), cancer vaccines, and bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these treatment approaches, emphasizing their mechanisms, limitations, and potential solutions, to overcome these bottlenecks. By integrating recent advancements and outlining critical challenges, this review aims to provide insights into future directions and guide the development of more effective treatment strategies for PC, with a specific focus on PDAC. Our work underscores the urgency of addressing the unmet needs in PDAC therapy and highlights promising areas for innovation in this field.

Liver recurrence after resection is one of the most common types of recurrence and is a risk factor for poor prognosis. The aim of this study was to identify risk factors for initial liver recurrence.

A total of 109 patients with resectable pancreatic ductal adenocarcinoma who underwent resection between 2015 and 2022 were included. The influence of clinicopathologic variables on liver recurrence was analyzed to create a novel scoring system to predict liver recurrence.

The liver recurrence rate was 24%, with 17% recurrence within 1 year. Patients with liver recurrence had an extremely poor prognosis within 1 year (MST 12.4 [95% CI, 5.7-19.1]). In multivariate analysis, R-PV, large tumor diameter ≥45 mm, and venous invasion were independent risk factors for early liver recurrence. When each of these risk factors was scored as 1 point, the 1-year liver recurrence rates by score were 0 (0%), 1 (9%), 2 (30%), and 3 (84%).

The risk factors for postoperative early liver recurrence were R-PV, a tumor diameter ≥45 mm, and pathological venous invasion. Surgery for pancreatic cancer with these factors may require special treatment, such as hepatic arterial injection.

Pancreatic cancer (PC) is the most lethal cancer. The prognosis of small PC (tumor ≤ 20 mm) is better than that of larger PC, indicating the importance of detecting early-stage PC for patient outcome. The aim of this study was to elucidate the molecular features in small PC (≤20 mm).

This study included 79 PC tumors (≤20 mm in pathological examination) resected between 2004 and 2022. c-Myc, Caveolin-1, Smad4, and Thrombospondin-1 were examined by immunostaining. These molecular alterations were compared in PC patients with tumor size ≤ 10 mm (n = 11) (14%) and 10 mm < tumor size ≤ 20 mm (n = 68) (86%). Mutation analyses of KRAS, PIK3CA, and BRAF were performed by pyrosequencing in 22 PCs.

PC with 10 mm < tumor size ≤ 20 mm showed significantly worse overall survival and disease-free survival than PC with tumor size < 10 mm (P = 0.024 and P = 0.028). Tumor c-Myc and stromal Caveolin-1 expressions were significantly increased in tumors larger than 10 mm (P = 0.02 and P = 0.04). c-Myc and Caveolin-1 expressions were associated with poor disease-free survival and overall survival. KRAS, PIK3CA, and BRAF mutation status did not differ between the 2 groups.

Tumor c-Myc and stromal Caveolin-1 overexpressions were detected in tumors larger than 10 mm. Their overexpressions were associated with worse prognosis even in small PC. These molecular alterations in small PC may be a clue for the detection of early-stage PC.

With the advent of improved chemotherapy options, neoadjuvant chemotherapy has gained acceptance as a multidisciplinary treatment approach for localized pancreatic ductal adenocarcinoma. This study aimed to clarify whether neoadjuvant chemotherapy with gemcitabine and S-1 influences preoperative nutritional status and postoperative outcomes, particularly in patients undergoing highly invasive pancreatic resection.

Patients with resectable pancreatic ductal adenocarcinoma who underwent pancreaticoduodenectomy as upfront surgery or after neoadjuvant chemotherapy with gemcitabine and S-1 between January 2015 and December 2022 were assessed. In addition to perioperative surgical outcomes, preoperative nutritional status was evaluated using serum albumin, controlling nutritional status, and prognostic nutritional index.

A total of 158 patients who underwent upfront pancreaticoduodenectomy and 119 who received neoadjuvant chemotherapy with gemcitabine and S-1 before pancreaticoduodenectomy were evaluated. Preoperative nutritional assessments (serum albumin, controlling nutritional status score, and prognostic nutritional index) showed no significant differences between groups, either at the initial consultation or immediately before surgery. No significant differences were observed in postoperative outcomes, including blood loss, operation time, and morbidity. The neoadjuvant chemotherapy with gemcitabine and S-1 group had a significantly greater rate of negative tumor margins (R0 resection rate 86% vs 74%, P = .018), and improved overall survival (hazard ratio, 0.41; 95% confidence interval, 0.25-0.67, P < .001) compared with the upfront pancreaticoduodenectomy group.

Neoadjuvant chemotherapy with gemcitabine and S-1 does not adversely impact preoperative nutritional status and enhances the effectiveness of pancreaticoduodenectomy for resectable pancreatic ductal adenocarcinoma, leading to improved pathologically curative resection rates and overall survival.

The ESPAC4 trial showed that adjuvant chemotherapy with gemcitabine plus capecitabine (GemCap) produced longer overall survival (OS) than gemcitabine monotherapy. Subsequently, the PRODIGE24-CCTG PA.6 trial showed even longer survival for modified fluorouracil, folinic acid, irinotecan, and oxaliplatin (mFOLFIRINOX) than gemcitabine but had more restrictive eligibility criteria. Our aim was to analyze the ESPAC4 survival on long-term follow-up.

The OS of 732 ESPAC4 patients comparing 367 randomly assigned to gemcitabine and 365 to GemCap was previously reported after a median follow-up time of 43.2 months (95% CI, 39.7 to 45.5) and 458 deaths. Analysis was now carried out after a median follow-up of 104 months (101-108) and 566 deaths.

The median OS was 29.5 months (27.5-32.1) for all patients, 28.4 months (25.2-32.0) in the gemcitabine group and 31.6 months (26.5-38.0) in the GemCap group (hazard ratio [HR], 0.83 [0.71 to 0.98]; P = .031). R0 patients given gemcitabine had a median survival of 32.2 months (27.9-41.6) compared with 49.9 months (39.0-82.3) for those given GemCap (HR, 0.63 [0.47 to 0.84]; P = .002). Lymph node-negative patients had significantly higher 5 year OS rates on GemCap (59% [49%-71%]) than gemcitabine (53% [42%-66%]; HR, 0.63 [0.41 to 0.98]; P = .04) but not those with positive lymph nodes (P = .225). The OS advantage for GemCap was retained in the PRODIGE24 subgroup of 193 (26.4%) ESPAC4 patients not eligible for PRODIGE24 with a median survival of 20.7 (16.2-27.3) months in patients allocated to gemcitabine compared with 25.9 (22.3-30.2) months for ineligible patients allocated to GemCap (HR, 0.71 [95% CI, 0.52 to 0.98]; χ2log-rank-1df = 4.31; P = .038).

GemCap is a standard option for patients not eligible for mFOLFIRINOX. Exploratory evidence suggests that GemCap may be particularly efficacious in R0 patients and also in lymph node-negative patients.

Neoadjuvant therapy is recommended for treating resectable pancreatic ductal adenocarcinoma (PDAC); however, its appropriate use in patients with resectable PDAC remains debatable.

This study aimed to identify independent poor prognostic factors and evaluate the clinical significance of neoadjuvant therapy in patients with resectable PDAC.

We retrospectively reviewed consecutive patients diagnosed with resectable PDAC at our institute between January 2003 and December 2022. We analyzed poor prognostic factors at the time of diagnosis in patients who underwent upfront surgery using the Cox proportional hazards model for overall survival (OS). The prognostic score was calculated by adding the individual prognostic factor scores.

Overall, 359 patients were included in this study, with 308 patients undergoing upfront surgery and the remaining 51 patients receiving neoadjuvant therapy. The R0 resection rate was significantly higher in the neoadjuvant therapy group (70.6%) than in the upfront surgery group (64.0%). Multivariate analysis in the upfront surgery group revealed the following independent poor prognostic factors: tumor size ≥ 35 mm, serum albumin level ≤ .5 g/dL, neutrophil-to-lymphocyte ratio ≥ 3.5, carbohydrate antigen 19-9 level ≥ 250 U/mL, and Duke pancreatic monoclonal antigen type 2 level ≥ 750 U/mL. Among patients with prognostic scores of 0-1 (n = 263), the intention-to-treat OS did not significantly differ between the neoadjuvant therapy and upfront surgery groups. Among those patients with a prognostic score of ≥ 2 (n = 96), the neoadjuvant therapy group had significantly longer intention-to-treat OS than the upfront surgery group.

Prognostic score-based stratification can help identify patients who could benefit from neoadjuvant therapy.

We herein report a case of pancreatic ductal adenocarcinoma (PDAC) that developed within the pancreatic duct and was initially diagnosed as an intraductal tubulopapillary neoplasm (ITPN). A 76-year-old man presented with weight loss and main pancreatic duct dilation. The imaging studies revealed a 30-mm hypovascular tumor within the main duct of the pancreatic head. An endoscopic examination with a biopsy revealed high-grade atypical epithelial cells with immunostaining patterns suggestive of ITPN. Following robot-assisted pancreaticoduodenectomy, postoperative pathology revealed conflicting features: nodular/cribriform infiltrations typical of ITPN and non-lobular replacement with scattered infiltrations characteristic of PDAC. A comprehensive genomic profiling test detected KRAS and TP53 mutations, leading to the final diagnosis of PDAC (fT3N1aM0, stage IIB). The patient received adjuvant S-1 chemotherapy and remained recurrence-free for 15 months post-surgery. This case highlights the diagnostic challenges of differentiating intraductal pancreatic tumors and demonstrates the utility of integrating genetic testing with conventional diagnostic modalities for an accurate diagnosis and appropriate treatment selection.

Pancreatic cancer is an aggressive tumor with high metastatic potential which leads to decreased survival rate and resistance to chemotherapy and immunotherapy. Nearly 90% of pancreatic cancer comprises pancreatic ductal adenocarcinoma (PDAC). About 80% of diagnoses takes place at the advanced metastatic stage when it is unresectable, which renders chemotherapy regimens ineffective. There is also a dearth of specific biomarkers for early-stage detection. Advances in next generation sequencing and single cell profiling have identified molecular alterations and signatures that play a role in PDAC progression and subtype plasticity. Most chemotherapy regimens have shown only modest survival benefits, and therefore, translational approaches for immunotherapies and combination therapies are urgently required. In this review, we have examined the immunosuppressive and dense stromal network of tumor immune microenvironment with various metabolic and transcriptional changes that underlie the pro-tumorigenic properties in PDAC in terms of phenotypic heterogeneity, plasticity and subtype co-existence. Moreover, the stromal heterogeneity as well as genetic and epigenetic changes that impact PDAC development is discussed. We also review the PDAC interaction with sequestered cellular and humoral components present in the tumor immune microenvironment that modify the outcome of chemotherapy and radiation therapy. Finally, we discuss different therapeutic interventions targeting the tumor immune microenvironment aimed at better prognosis and improved survival in PDAC.

S-1 is an orally active anticancer drug known to cause ocular adverse events (AEs), including lacrimal passage obstruction and corneal complications. This study investigated tear concentrations of 5-fluorouracil (5-FU) and tegafur (FT) in patients receiving S-1 treatment and their relationship with ocular AEs.

Multicenter prospective cohort study.

We recruited patients scheduled for S-1 chemotherapy. After initial ophthalmologic examinations at enrollment, serial examinations were performed during the courses of S-1 administration for up to 1 year. Tear samples were collected using Schirmer test strips at the end of the first course of S-1 treatment. 5-FU and FT concentrations were measured using high-performance liquid chromatography.

The study cohort comprised 94 patients among whom 38 (40.4%) developed ocular AEs, including 32 (34.0%) corneal AEs, 13 (13.8%) lacrimal AEs, and 7 (7.4%) patients who developed both. The tear FT concentrations in the ocular AE group were significantly higher compared with the group without ocular AEs (3.15 ± 3.09 vs. 1.86 ± 1.56 µg/mL; p = 0.017). There was no difference in tear 5-FU concentration between the 2 groups. The FT concentration in tears in the corneal and lacrimal AE groups was significantly higher than in the group without ocular AEs (p = 0.013 and 0.030, respectively).

FT concentration in tears due to oral S-1 therapy is associated with corneal or lacrimal AEs. Measuring FT concentration in tears or plasma may be useful for predicting the onset of ocular AEs.

With progress in pancreatic surgery, a preservation of residual organ function has become more important. Pancreatic malignancies are occasionally accompanied by chronic pancreatitis (CP) and pancreatolithiasis (PL). Longitudinal pancreatojejunostomy (LPJ) is reportedly a useful method of surgical management in cases of CP with PL. We describe a patient with pancreatic head intraductal papillary mucinous carcinoma (IPMC) concomitant with PL, who underwent subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) and LPJ for reconstruction.

A man in his 70s was referred to our hospital with a pancreatic head tumor. He had been treated for CP, diabetes mellitus, and chronic kidney disease. Imaging revealed a cystic pancreatic head tumor with a solid component that was histologically confirmed as IPMC. In addition, multiple calcifications suggestive of PL were observed in the pancreatic body and tail. SSPPD and LPJ were performed to excise the PL as much as possible and preserve the residual pancreatic function. The postoperative course was uneventful, and no abdominal symptoms or tumor recurrences were observed for approximately 8 months after surgery.

This patient with IPMC with residual pancreatic PL was treated with SSPPD and LPJ to maximize the residual pancreatic function and reduce the occurrence of postoperative pancreatitis.

The aim of this study was to investigate the feasibility and effectiveness of pancreatectomy with arterial resection/divestment for pancreatic cancer with arterial involvement in the modern era of multidisciplinary treatment.

Patients who underwent pancreatectomy with arterial resection/pancreatectomy with arterial divestment for pancreatic cancer with arterial involvement from 2010 to 2021 were retrospectively analysed, and outcomes were compared between the former (2010-2015) and latter interval (2016-2021). Survivals were compared by univariable and multivariable analyses.

Among 203 patients included, 76 underwent pancreatectomy with arterial resection and 127 underwent pancreatectomy with arterial divestment. Compared with the former interval, more patients received preoperative chemotherapy (26.6% (n = 21) versus 95% (n = 118), P < 0.001), and underwent pancreatectomy with arterial resection (30.4% (n = 24) versus 41.9% (n = 52), P = 0.287) in the latter interval. The major morbidity rate and pancreatic fistula decreased in the latter interval (major morbidity rate: P = 0.040; pancreatic fistula: P = 0.006), even among patients undergoing pancreatectomy with arterial resection (major morbidity rate: P = 0.013; pancreatic fistula: P < 0.001). Patients in the latter interval had better overall survival (26.0 versus 48.2 months, P = 0.001), even among patients undergoing pancreatectomy with arterial resection (22.0 versus 45.1 months, P = 0.076).

Within the context of modern multidisciplinary treatment, radical resection including arterial resection should be justified for patients with pancreatic cancer with arterial involvement, considering the acceptable perioperative risk and prolonged survival.

The effectiveness and preferred reconstruction methods of pancreatectomy associated with vein resection (PAVR) for pancreatic cancer, especially for the extensive portal vein/superior mesenteric vein (PV/SMV) resections (more than 4 cm), are still subjects of debate. The aim of this study is to evaluate the safety and feasibility of PAVR by analyzing data from two large institutions from different regions.

From 2008 to 2018, we identified consecutive series of patients with pancreatic cancer who underwent PAVR at Karolinska University Hospital (KUH), Sweden, and Cancer Institute Hospital, Japanese Foundation of Cancer Research (JFCR), Japan. Both institutions adopted the artery-first approach to enhance surgical precision. This study compared the short- and long-term outcomes, vein resection types, and reconstruction methods between the two centers.

A total of 506 patients who underwent PAVR were identified, 211 patients were from KUH and 295 patients were from JFCR. A higher incidence of total pancreatectomy was identified at KUH (24.6 % vs 0.3 %). There were no significant differences in intraoperative estimated blood loss (KUH: 630 ml, JFCR: 600 ml), severe complications rate (8.5 %, 5.1 %), and mortality (2.4 %, 0.7 %). Primary end-to-end anastomosis was primarily performed even if the length of PV/SMV resection was 5 cm or more and achieved successfully with acceptable patency (No thrombus rate: overall cases, 98.0 %; 5 cm or more, 93.5 %).

We report favorable outcomes of PAVR for pancreatic cancer from two high-volume centers in the east and west. Primary end-to-end anastomosis was safe and feasible even if the length of PV/SMV resection was 5 cm or more.

Gemcitabine/cisplatin (GemCis) was the long-standing first-line treatment for advanced biliary tract cancers (BTCs). Following positive results from the TOPAZ-01 and KEYNOTE-966 trials, immune checkpoint inhibitors (ICIs) combined with chemotherapy are now the standard of care. We aim to compare the efficacy of first-line therapies for advanced BTCs.

Our systematic review included studies from five databases focusing on English-language articles published between January 2010 and June 2024. We included randomized clinical trials (RCTs) that featured GemCis in a treatment arm for treatment-naive adults with advanced BTCs. The primary endpoints were overall survival (OS) and progression-free survival. We conducted a one-stage meta-analysis using reconstructed survival data, Cox-based models, and restricted mean survival time (RMST).

After screening 8,797 studies, 17 RCTs were selected, involving a total of 4,584 patients. Of these, 2,140 (46.7%) received GemCis. The majority (68.9%) were diagnosed with intrahepatic or extrahepatic cholangiocarcinoma, and 80% had metastatic disease at the time of treatment. The pooled median OS in the GemCis group was 11.6 months (95% CI 11.3-12.2 months). GemCis plus pembrolizumab (hazard ratio [HR] 0.99, 95% CI 0.98-0.99; p <0.001), GemCis plus durvalumab (HR 0.98, 95% CI 0.97-0.99; p = 0.015), GemCis plus S-1 (HR 0.97 95% CI 0.95-0.99; p <0.001), and GemCis plus nab-paclitaxel (HR 0.98, 95% CI 0.98-0.99; p <0.001) demonstrated superior OS compared with GemCis alone. These combinations also showed increases in RMST by +1.1, +2.5, +2.8, and +2.1 months, respectively. In terms of progression-free survival, GemCis with ICIs (HR 0.91, 95% CI 0.78-0.94; p <0.001), GemCis plus S-1 (HR 0.98, 95% CI 0.96-0.99; p = 0.003), and GemCis plus nab-paclitaxel (HR 0.98, 95% CI 0.97-0.99; p <0.001) also demonstrated superiority, with corresponding RMST increases of +0.7, +1.9, and +2.5 months, respectively.

Despite incremental advancements, a breakthrough in advanced BTC treatment remains elusive. Further improvements in treatment efficacy may require biomarker identification to optimize combinational therapies for better patient selection.

This study analyzed recent RCTs, including KEYNOTE-966, TOPAZ-1, NIFE, and SWOG 1815, involving 4,584 patients with advanced biliary tract cancer. A meta-analysis of 17 treatment arms, using reconstructed survival data, confirmed the modest survival benefit of GemCis plus ICIs, supporting its guideline adoption. The findings, however, highlight the need for biomarker identification and better patient selection.

The effect of adjuvant chemotherapy following resection of pancreatic adenocarcinoma after preoperative (m)FOLFIRINOX (combination leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin in full or modified dosing) chemotherapy on overall survival (OS) is unclear because current studies do not account for the number of cycles of preoperative chemotherapy and adjuvant chemotherapy regimen.

To investigate the association of adjuvant chemotherapy following resection of pancreatic adenocarcinoma after preoperative (m)FOLFIRINOX with OS, taking into account the number of cycles of preoperative chemotherapy and adjuvant chemotherapy regimen.

This retrospective cohort study included patients with localized pancreatic adenocarcinoma treated with 2 to 11 cycles of preoperative (m)FOLFIRINOX followed by resection across 48 centers in 20 countries from 2010 to 2018. Patients who died within 3 months after surgery were excluded (landmark). Data were analyzed from February 1 to December 31, 2023.

Preoperative (m)FOLFIRINOX chemotherapy followed by resection and eventually followed by adjuvant chemotherapy.

The primary outcome was OS, calculated from the 3-month landmark. Cox regression analysis, including interaction analyses, was performed to investigate the association of adjuvant chemotherapy with OS.

Overall, 767 patients were included after resection of pancreatic adenocarcinoma (median [IQR] age, 62 [55-67] years; 404 [52.7%] male). Adjuvant chemotherapy was independently associated with prolonged OS (hazard ratio [HR], 0.66; 95% CI, 0.49-0.87), confirmed by adjusted OS curves. The interaction analysis to assess estimated treatment effect across subgroups was not statistically significant. The forest plot and interaction test suggest that the association of adjuvant chemotherapy was lower among patients receiving 8 or more cycles of preoperative (m)FOLFIRINOX, those who had radiological response, and those with ypN0 disease. Compared to no adjuvant chemotherapy, both adjuvant (m)FOLFIRINOX (HR, 0.57; 95% CI, 0.40-0.80) and other multiagent adjuvant regimens (HR, 0.61; 95% CI, 0.41-0.92) were associated with prolonged OS, whereas single-agent adjuvant chemotherapy was not (HR, 0.75; 95% CI, 0.55-1.03).

In this cohort study, adjuvant (m)FOLFIRINOX and other multiagent chemotherapy regimens were associated with improved OS following resection of localized pancreatic adenocarcinoma after preoperative (m)FOLFIRINOX, whereas single-agent adjuvant chemotherapy was not. The impact of adjuvant chemotherapy on OS may be lower in subgroups such as patients with 8 or more preoperative cycles of (m)FOLFIRINOX, those having radiological response, and those with ypN0.

A fundamental challenge for cancer vaccines is to generate long-lived functional T cells that are specific for tumour antigens. Here we find that mRNA-lipoplex vaccines against somatic mutation-derived neoantigens may solve this challenge in pancreatic ductal adenocarcinoma (PDAC), a lethal cancer with few mutations. At an extended 3.2-year median follow-up from a phase 1 trial of surgery, atezolizumab (PD-L1 inhibitory antibody), autogene cevumeran1 (individualized neoantigen vaccine with backbone-optimized uridine mRNA-lipoplex nanoparticles) and modified (m) FOLFIRINOX (chemotherapy) in patients with PDAC, we find that responders with vaccine-induced T cells (n = 8) have prolonged recurrence-free survival (RFS; median not reached) compared with non-responders without vaccine-induced T cells (n = 8; median RFS 13.4 months; P  =  0.007). In responders, autogene cevumeran induces CD8+ T cell clones with an average estimated lifespan of 7.7 years (range 1.5 to roughly 100 years), with approximately 20% of clones having latent multi-decade lifespans that may outlive hosts. Eighty-six percent of clones per patient persist at substantial frequencies approximately 3 years post-vaccination, including clones with high avidity to PDAC neoepitopes. Using PhenoTrack, a novel computational strategy to trace single T cell phenotypes, we uncover that vaccine-induced clones are undetectable in pre-vaccination tissues, and assume a cytotoxic, tissue-resident memory-like T cell state up to three years post-vaccination with preserved neoantigen-specific effector function. Two responders recurred and evidenced fewer vaccine-induced T cells. Furthermore, recurrent PDACs were pruned of vaccine-targeted cancer clones. Thus, in PDAC, autogene cevumeran induces de novo CD8+ T cells with multiyear longevity, substantial magnitude and durable effector functions that may delay PDAC recurrence. Adjuvant mRNA-lipoplex neoantigen vaccines may thus solve a pivotal obstacle for cancer vaccination.

Radiation therapy (RT) for locally advanced pancreatic cancer (LAPC) continues to be controversial. Advances in both systemic therapy and RT techniques have changed the landscape of LAPC management in recent years. Clinical outcomes of ablative RT have been encouraging, and randomized clinical trials may clarify the role of RT for LAPC. We present a contemporary critical review of key aspects regarding optimal patient selection, radiation dose escalation techniques, novel radiosensitizers and radioprotectors, and treatment response assessment for LAPC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis. When it metastasizes to the liver, treatment options become particularly limited and challenging. Current treatment options for liver metastatic PDAC are limited, and chemotherapy alone often proves insufficient. Immunotherapy, particularly programmed cell death 1 (PD-1) inhibitors like sintilimab, shows potential efficacy for various cancers but has limited reports on PDAC. This study compares the efficacy and safety of sintilimab plus S-1 and gemcitabine vs S-1 and gemcitabine alone in liver metastatic PDAC.

To explore the feasibility and effectiveness of combined PD-1 inhibitor sintilimab and S-1 and gemcitabine (combination group) vs S-1 and gemcitabine used alone (chemotherapy group) for treating liver metastatic pancreatic adenocarcinoma.

Eligible patients were those with only liver metastatic PDAC, an Eastern Cooperative Oncology Group performance status of 0-1, adequate organ and marrow functions, and no prior anticancer therapy. Participants in the combination group received intravenous sintilimab 200 mg every 3 weeks, oral S-1 40 mg/m² twice daily on days 1-14 of a 21-day cycle, and intravenous gemcitabine 1000 mg/m² on days 1 and 8 of the same cycle for up to eight cycles or until disease progression, death, or unacceptable toxicity. Participants in the chemotherapy group received oral S-1 40 mg/m² twice daily on days 1-14 of a 21-day cycle and intravenous gemcitabine 1000 mg/m² on days 1 and 8 of the same cycle for up to eight cycles. Between June 2020 and December 2021, 66 participants were enrolled, with 32 receiving the combination treatment and 34 receiving chemotherapy alone.

The group receiving the combined therapy exhibited a markedly prolonged median overall survival (18.8 months compared to 10.3 months, P < 0.05) and progression-free survival (9.6 months vs 5.4 months, P < 0.05). compared to the chemotherapy group. The incidence of severe adverse events did not differ significantly between the two groups (P > 0.05).

The combination of PD-1 inhibitor sintilimab with S-1 and gemcitabine demonstrated effectiveness and safety for treating liver metastatic PDAC, meriting further investigation.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers, characterized by late diagnosis, rapid progression, and limited therapeutic options. Despite advancements, only 20% of patients are eligible for surgical resection at diagnosis, the sole curative treatment. Multidisciplinary evaluation is critical to optimize care, stratifying patients based on resectability into resectable, borderline resectable, locally advanced, and metastatic stages. Preoperative imaging, such as computed tomography (CT) and endoscopic ultrasound (EUS), remains central for staging, for vascular assessment, and tissue acquisition. Endoscopic and systemic approaches are pivotal for addressing complications like biliary obstruction and improving outcomes. Endoscopic retrograde cholangiopancreatography (ERCP) has been considered for years the gold standard for biliary drainage, although EUS-guided drainage is increasingly utilized due to its efficacy in both resectable and unresectable disease. Systemic therapies play a key role in neoadjuvant, adjuvant, and palliative settings, with ongoing trials exploring their impact on survival and resectability chance. This review highlights the evolving multidisciplinary approaches tailored to the disease stage, focusing on biliary drainage techniques, systemic therapies, and their integration into comprehensive care pathways for PDAC. The continuous refinement of these strategies offers incremental survival benefits and underscores the importance of personalized, multidisciplinary management.

Despite the benefits of surgical resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC), over 30 % of patients fail to complete adjuvant oncological treatment. Whether postoperative complications affect chemotherapy completion rates and overall survival remains uncertain. We hypothesized that postoperative complications would be associated with chemotherapy delays, omission, and reduced overall survival (OS).

This was a retrospective analysis of patients undergoing pancreaticoduodenectomy for PDAC from 2008 to 2022 to assess whether serious surgical complications, defined as Clavien Dindo Grade 3b or higher, were associated with the omission or delay of adjuvant oncologic treatment as well as OS.

A total of 920 patients were available for analysis. Pancreatic and bile leakage were associated with risk of chemotherapy omission (OR 1.97 [CI 95 % 1.25-3.12], p = 0.004 and OR 1.96 [CI 95 % 1.04-3.67], p = 0.032, respectively). No delay of adjuvant chemotherapy >90 days nor change in OS was found.

Major surgical complications influence the likelihood of omitting adjuvant chemotherapy but not delaying it > 90 days. Patients with pancreatic or bile leakage were at greater risk of not completing planned chemotherapy but had the same OS.