bluuebunny/crossref_metadata_2025_split huggingface dataset:
FOLFIRINOX plus high intensity focused ultrasound for locally advanced/borderline resectable pancreatic ductal adenocarcinoma: A prospective single arm phase II trial.
Authors: Lee Dong Ho , Lee Jae Young , Lee Sang Hyub , Jang Jin-Young 
Published: January 2024

670 Background: FOLFIRINOX has been the standard regimen for locally advanced pancreatic cancer (LAPC) for palliation and borderline resectable pancreatic cancer (BRPC) for neoadjuvant treatment. According to the results of animal studies, concurrent use of high intensity focused ultrasound (HIFU) and chemotherapy can enhance the drug delivery to the target tissue. In this phase II trial, we aimed to evaluate the safety and therapeutic efficacy of FOLFIRINOX plus HIFU for patients with LAPC or BRPC. Methods: This study was designed as a prospective single center phase II trial (Study identifier: NCT05262452). We prospectively enrolled 60 patients (M:F=35:25; median age, 67.0 years old) with LAPC (n=23) or BRPC (n=37). The median tumor size was 4.0 cm (Interquartile range, 2.7-4.6). All patients were treated by FOLFIRINOX (oxaliplatin, 85mg/m2 of body-surface area; irinotecan, 180mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2 given as a bolus followed by 2400 mg/m2 given as a 46-hour continuous infusion) every 2 weeks until disease progression. HIFU was combined in the first 4 cycles of chemotherapy with following parameters: intensity of 2.0 kw/cm2, duty cycle of 1%, exposure time of 3 seconds and PRF of 10Hz. Follow-up contrast enhanced CT was taken every 4 cycles for the response evaluation using response evaluation criteria for solid tumor 1.1. Overall survival (OS) and progression-free survival were estimated using Kaplan-Meier method. All analyses were intention-to-treat. Results: Two patients withdrew the consent, and two patients could not complete planned 4 cycles of FOLFIRINOX plus HIFU treatment owing to sepsis from severe neutropenia related to chemotherapy. Among 56 patients who completed the 4 cycle of FOLFIRINOX plus HIFU and continued chemotherapy, partial response was achieved in 36 patients (60.0%, 36/60), and stable disease in 20 patients. Regarding the adverse effect (AE), 32 of 60 patients experienced grade 3 (n=22) or grade 4 (n=10) AE, all of them were related to FOLFIRINOX chemotherapy. No AE related to HIFU was observed. The estimated OS was 94.8%, 75.9% and 67.6% at 6-, 12- and 18 months, respectively. Regarding the PFS, the 6-, 12- and 18-month PFS was 91.9%, 70.3% and 56.2%, respectively. Conclusions: FOLFIRINOX plus HIFU was safe and effective treatment for LAPC/BRPC, providing 60.0% of partial response rate without any additional AE to chemotherapy. Clinical trial information: NCT05262452 .
Prognostic factors for GEM + nab-PTX combination therapy in elderly patients with pancreatic cancer.
Authors: Watabe Kazuki , Ohno Izumi , Sakai Miho , Takahashi Tomoya , Yamada Nana , Tohyama Shodai , Sekine Yu , Sugihara Jihei , Ohuchi Mayu , Nagashima Hiroki , Takahashi Koji , Okitsu Kohichiro , Kan Motoyasu , Ohyama Hiroshi , Ohtsuka Masayuki , Kato Naoya 
Published: January 2024

678 Background: Japanese Clinical Practice Guidelines for Pancreatic Cancer 2022 recommends gemcitabine (GEM) + nab-paclitaxel (nab-PTX) therapy (GnP regimen) as the first line chemotherapy for elderly patients with pancreatic cancer. In Japan, it is reported that about 69% of pancreatic cancer patients are elderly, and Only few group reported the safety of GnP regimen. In this study, we investigated the anti-tumor efficacy and prognostic factors of GnP regimen in patients with pancreatic cancer at our hospital, with a particular focus on age. Methods: 160 patients who started GnP therapy as the first line treatment for unresectable pancreatic cancer between February 2016 and December 2021 were included in the study. 70 years of age or older was defined as elderly, and patient background and treatment efficacy were compared in two groups: non-elderly patients (n=84) and elderly patients (n=76). Prognostic factors were also compared between the overall population and the elderly. Results: Patients with a primary lesion in the pancreatic head were 32 (38.1%) of the non-elderly patients and 35 (46.1%) of the elderly patients. 60 patients (71.4%) of the non-elderly and 38 (50.0%) of the elderly had distant metastases. The median overall survival was 16.0 months for the non-elderly and 17.7 months for the elderly, with no significant difference (p=0.93). Significant prognostic factors for the overall subject population were ECOG PS (HR 1.80, p=0.019), liver metastasis (HR 2.36, p<0.01), CRP (HR 1.91, p<0.01) and NLR (HR 2.65, p<0.01). The only significant prognostic factor in the elderly was liver metastasis (HR 2.59, p<0.01). Conclusions: GnP regimen in pancreatic cancer can be expected to have the same antitumor effect in elderly patients as in non-elderly patients. However, significant prognostic factors were reduced in the elderly, we need to identify specific factors to determine the indication for treatment in the elderly patients.
Pulsed low dose rate radiation to mitigate tumor-permissive responses in pancreatic cancer-associated fibroblasts: Introducing the HOST-factor.
Authors: Cukierman Edna , Franco-Barraza Janusz , Luong Tiffany , Raghavan Kristopher , Wong Jessica Karen , Vendramini Costa Debora Barbosa , Francescone Ralph , Gardiner Jaye C. , Reddy Sanjay S. , Handorf Elizabeth A. , Meyer Joshua E. 
Published: January 2024

682 Background: Pancreatic ductal adenocarcinoma (PDAC) features a distinctive tumor microenvironment comprising cancer-associated fibroblasts (CAFs) and their self-produced extracellular matrix (ECM), forming functional CAF units (CAF u). The current total neoadjuvant therapy (TNT), involving conventional chemoradiotherapy (CRT), yields suboptimal responses while promoting a tumor-permissive CAF u state. To address this, we explored pulsed low dose rate radiation (PLDR)-based TNT, as an alternative to CRT, to treat three-dimensional in vivo-like human PDAC CAF u cultures. We assessed gemcitabine combined with PLDR versus CRT using theHOST Factor, a “harmonized output of stroma traits” factor, comprising several established CAF u functional indicators, which inform on the functional status of the PDAC microenvironment. Methods: The unique CAF u functional values used corresponded to: i) ECM anisotropy; ii) persistent cell-ECM signaling; iii) sustained cytokine-induced activation; iv) cytoskeletal bundling; and v) systemic features of fibroblastic activation. The validity of the resultant HOST factor was assessed using the unit’s ECM ability to elicit fibroblastic activation, indicated by a high αSMA/F-actin ratio value. Results: Ex-vivo CRT led to a HOST factor that was 2-fold greater than chemotherapy alone (p=0.6), which was functionally gauged as a tumor-permissive CAF u. In contrast, PLDR averted CRT-induced tumor-permissive response and established a 6-fold lower HOST factor, suggestive of a “normalized” CAF u, when compared to the HOST factor value established when using conventional TNT (P=0.0016 vs. CRT, and P= 0.0086 vs. gemcitabine alone). The multi-parameter HOST factor validity was confirmed as CRT treated CAF u’s ECM activated human pancreatic fibroblasts (αSMA/F-actin = 70% ± 29) while PLDR-treated CAF u's ECM failed to do so (αSMA/F-actin = 32% ± 26), reaching a 30% mean rank difference (P <0.0001). Conclusions: PLDR mitigates conventional CRT-based TNT-induced tumor-permissive responses, restoring the fibroblastic units' tumor-suppressive function. These results lend support to a phase 1 trial designed to evaluate whether radiation with PLDR-based TNT, constitutes a safe and more effective treatment for PDAC patients. The novel HOST factor is being used to appraise specimens from NCT04452357.
Genomics and transcriptomics of pancreatic adenosquamous carcinoma.
Authors: Kania Brooke Elizabeth , Baca Yasmine , Riedlinger Gregory , Goel Sanjay , Lou Emil , Weinberg Benjamin Adam , Khushman Moh'd M. , Xiu Joanne , Gulhati Pat 
Published: January 2024

691 Background: Pancreatic cancer (PC) is anticipated to become the 2nd leading cause of cancer-related deaths by 2030. Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of PC with histology including squamous adenomatous features (≥30% squamous histology), while pancreatic squamous cell cancer (PSCC) consists purely of squamous cells. We evaluated genomic, transcriptomic and prognostic differences between PASC, PSCC and pancreatic ductal adenocarcinoma (PDAC). Methods: 8951 PC tumors (83 PASC, 22 PSCC & 8846 PDAC) tested at Caris Life Sciences with WTS (Illumina, Novaseq) and NextGen DNA sequencing (NextSeq, 592 genes and NovaSeq, WES) and IHC were analyzed. Immune cell fraction was calculated by QuantiSeq. Overall survival (OS) analysis (time of tissue collection to last contact) was obtained from insurance claims and calculated with KM method. Statistical significance was determined using Chi-square/Fisher-Exact and adjusted for multiple comparisons (q<0.05). Results: No age or sex differences were seen between PDAC (median 68yo) and PASC (median 68.5yo), however PSCC was more prevalent in younger pts (median 62.5yo, q<0.05). Mutation rates of CDKN1B (3% vs 0.2%), SF3B1 (8 vs 2%), PTEN (5 vs 0.8%), BCL9 (4 vs 0.4%), AXIN1 (4 vs 0.2%) and CASP8 (3 vs 0.2%) and amplifications of AKT2 (5 vs 2%), ZNF384 (1 VS 0.1%), HMGA2 (7 vs 0.7%) and ROS1 fusions (1 vs 0.04%) all trended higher in PASC than PDAC (p<0.05). Several YAP signaling and squamous differentiation genes were significantly differentially expressed among histologies (table). PD-L1 IHC was higher in PASC vs PDAC (37 vs 14%, q<0.05); with a trend towards higher MSI-H (6 vs 1%) & TMB-H (6 vs 2%) in PASC vs PDAC (p<0.05). Higher infiltration of CD4+ T cells into the TME was seen in PASC vs PDAC (non-zero %, 73% vs 23%, q<0.05). Several immune genes ( CD274, IDO1, LAG3, & CTLA4) had higher expression in PASC vs PDAC (fold change 1.3-3.1, q<0.05). The MAP kinase pathway activation score (MPAS) was lower in PASC vs PDAC (median score -0.48 vs 0.25), while the IFN gamma signature was higher in PASC vs PDAC (median -0.24 vs -0.33) [both q<0.05]. There was increased OS for PASC compared to PSCC (12.6 vs 4.7 mo, HR=0.43, CI=0.25-0.75, p=0.002); no significant difference in OS was observed between PASC and PDAC. Conclusions: This is the largest molecular profiling analysis of PASC, which is characterized by unique genomic alterations, and is associated with higher PD-L1 expression, immune related gene expression, CD4+ T cell infiltration and IFN gamma signature, and lower MAPK activation. PASC is associated with better OS compared to PSCC. These findings may provide subtype-specific therapeutic opportunities for PASC and PSCC pts.[Table: see text]
The impact of Wnt pathway alterations including RNF43, GNAS, CTNNB1, and APC on prognosis and potential therapeutic vulnerability in pancreatic adenocarcinoma (PDAC).
Authors: Takebe Naoko , Blais Edik Matthew , Huynh Jasmine , Thach Dzung , de Arbeloa Patricia Miren , Matrisian Lynn McCormick , Petricoin Emanuel , Pishvaian Michael J. , Chung Vincent , Boland Patrick M , Yaeger Rona , Wadlow Raymond Couric , Hendifar Andrew Eugene , Nevler Avinoam , Cannon Timothy Lewis 
Published: January 2024

698 Background: Several Wnt pathway genes (RNF43, GNAS, CTNNB1, APC) are mutated in PDAC but their clinical implications remain unclear. Both RNF43, a membrane E3 ubiquitin ligase that negatively regulates Wnt via FZD, and GNAS, a mediator of GPCR signaling, are enriched in IPMN-associated PDAC whereas CTNNB1 is a hallmark of solid pseudopapillary neoplasms. Here, we retrospectively analyzed progression-free survival (PFS) and overall survival (OS) in a PDAC cohort to understand potential therapeutic and prognostic differences between tumors with (MUT) or without (WT) Wnt pathway mutations. Methods: We analyzed longitudinal outcomes across 774 patients (pts) with NGS results from Perthera’s Real-World Evidence database who received at least 1 line of therapy in the advanced setting for PDAC. PFS was evaluated from initiation of 1st line for advanced disease until discontinuation due to disease progression. Hazard ratios and p-values were computed via Cox regression when comparing PFS within subsets that received either 1st line FOLFIRINOX (FFX) or 1st line gemcitabine/nab-paclitaxel (GA). Differences in frequencies of genomic alterations outside the Wnt pathway were analyzed by Fisher’s exact test. Results: Within the analysis cohort (N = 774), Wnt pathway alterations were present in 72 (9.3%) of PDAC tumors based on mutations in either RNF43 (4%), GNAS (3%), CTNNB1 (<1%), or APC (2%). Median OS (relative to advanced diagnosis) was significantly longer in the MUT subgroup compared to WT (Table). Median PFS on 1st line GA was significantly longer in MUT pts, and a similar insignificant trend was noted for PFS on 1st line FFX (Table). MSI-high and PIK3CA mutations were enriched for co-occurrence with Wnt pathway alterations whereas common PDAC mutations in KRAS and TP53 were less frequent in MUT pts (Table). Gene-specific trends and potential confounders will be discussed in the context of multivariate OS/PFS analyses. Conclusions: The presence of Wnt pathway alterations identifies a subgroup of advanced PDAC with improved PFS and OS.[Table: see text]
Association of longitudinal changes of genomic alteration of circulating tumor DNA with treatment response in pancreatic cancer.
Authors: Choi Jin Ho , Lee Sang Hyub , Paik Woo Hyun , Kim Junyeol , Lee Tae Seung , Lee Myeong Hwan , Cho In Rae , Ryu Ji Kon , Kim Yong-Tae 
Published: January 2024

701 Background: Recently, the evaluation of circulating tumor DNA (ctDNA) in pancreatic cancer (PC) patients has gained attention for detection of mutation profile. However, the concordance between tissue next-generation sequencing (NGS) and ctDNA NGS remains unclear. Additionally, the dynamics of genomic alterations during treatment or disease progression are not well understood. Methods: In this prospective cohort study conducted at Seoul National University Hospital from Jan 2022, tissue samples from endoscopic ultrasound-guided fine needle biopsies and blood samples were collected from PC patients. Genomic DNA from the treatment naïve primary tissue and ctDNA from the blood obtained before any treatment and during follow-up with anti-cancer treatment were obtained. Genomic alternation was analyzed based on targeted NGS based panel deep sequencing including 41 genes. Results: The concordance of genomic alteration profiles between tissue NGS and ctDNA NGS was evaluated in 55 patients, and the mutation detection rate of patients who were diagnosed as stage I or II disease were 100% (14 of 14) in tissue NGS and 86% (12 of 14) in ctDNA NGS. That of patients who were diagnosed as stage III or IV disease was 92.7% in tissue NGS (38 of 41) and 90% (37 of 41) in blood ctDNA NGS. Among the study patients, the longitudinal changes of genomic mutation profile were evaluated in the patients at the first treatment response assessment, and patients with progressive disease showed significantly greater amounts of mutations including newly detected Tier1/2 variants than baseline and the previous response assessment. Conclusions: In conclusion, there is comparable mutation detection between tissue genomic DNA and blood ctDNA. The significant increase in ctDNA mutations during disease progression suggests their association with immune evasion and cancer evolution. Further studies utilizing our prospective cohort are needed to explore clinical implications of these results.
Clinical and prognostic characteristics of early onset metastatic pancreatic cancer.
Authors: Pretta Andrea , Giampieri Riccardo , Nichetti Federico , Ziranu Pina , Lupi Alessio , Cimbro Erika , Andena Paola , Felicetti Cristiano , Pircher Chiara Carlotta , Gusmaroli Eleonora , Donisi Clelia , Balconi Francesca , Mariani Stefano , Lai Eleonora , Puzzoni Marco , Pusceddu Valeria , Berardi Rossana , Niger Monica , Scartozzi Mario 
Published: January 2024

702 Background: In the last decade several studies have shown an increase in the incidence of early-onset PDAC (EO-PDAC), conventionally defined as cancer that occurs in adults between the ages of 18 and 49. Clinical and prognostic data on this setting are limited and conflicting. The aim of our study was to evaluate the clinical, and prognostic differences in a large group of patients with early onset mPDAC. Methods: We retrospectively collected data from 368 patients affected with metastatic pancreatic ductal adenocarcinoma, from 3 different Italian Institutions. All patients had one or more metastatic sites, and received first-line chemotherapy. The main objective of the study was to evaluate the median overall survival in EO-PDAC patients compared to late onset PDAC (LO-PDAC), while secondary endpoint was evaluations of mPFS. Statistical analysis was performed with the MedCalc package. Results: 30 (8,1%) patients were early onset and 338 (91,9%) were late onset; median age was 46 (±5) and 68 (±8), respectively. M/F ratios were 1:1 in both group. In the overall population mOS was significantly lower in EO-PDAC patients: 10,0 versus 15,0 months ( p = 0,03). Furthermore, mPFS was significantly lower in EO-PDAC patients: 5,0 versus 8,0 months ( p = 0,04). ORR obtained from 244 pts were: 11% in EO-PDAC and 24,7% in LO-PDAC. Conclusions: The results of our work, although limited by the retrospective nature of the study, showed a worse prognosis for patients with early onset PDAC compared to late onsets. Further investigations will be needed to better understand this growing group of patients from a molecular and therapeutic point of view.
Epidemiological characteristics of patients with pancreatic cancer with and without diabetes mellitus: A retrospective cohort study.
Authors: Eichinger Sarah Elizabeth , Nieto Dominguez Alejandro , Guifarro Rivera Daniel , Turk Ekrem , Pan Chun-Wei 
Published: January 2024

705 Background: Pancreatic cancer accounts for approximately 3% of new cancers diagnosed in the US and more than 8% of all cancer deaths. Despite the increasing incidence, there are few indicated screenings, mostly in patients with genetic mutations. Pancreatic cancer is associated with several risk factors including tobacco use, family history, heavy alcohol use, and diabetes mellitus (DM). In the US, more than 11% of adults have a diagnosis of diabetes and incidence is projected to rise over the coming years. Given the risk of DM associated with pancreatic cancer, establishing preventative measures, early intervention, and appropriate follow up for diabetic control could be an important step in decreasing the risk of pancreatic cancer. This study examines the demographic characteristics of patients with a diagnosis of pancreatic cancer with and without DM. Methods: We used the 2016-2019 Nationwide Inpatient Sample database, the largest all-payer inpatient care database in the US, to stratify all patients admitted with a diagnosis of pancreatic cancer, with and without DM, to further characterize their epidemiological characteristics. Results: Characteristics of patients with and without DM and pancreatic cancer are shown in the table. There were 150,275 patients diagnosed with pancreatic cancer, of which 44,170 (29%) had a concomitant diagnosis of DM. Of patients with both pancreatic cancer and DM, 53% were women (51% in patients without DM), 64% were white (70% in patients without diabetes), and 63% had Medicare for insurance (60% in patients without DM). Conclusions: Of patients with pancreatic cancer 29% had a concomitant diagnosis of DM(p=0.00). Epidemiological characteristics of patients with pancreatic cancers with and without DM such as age, sex, and insurance status were similar between both groups. However, there was a decreased percentage of Caucasian patients with pancreatic cancer and DM compared to those without DM. Given the association of diabetes with pancreatic cancer, and rising incidence of patients with diabetes in the US, emphasis on diabetes prevention and control may be an important factor in reducing the incidence pancreatic cancer. This study also suggests the need for further research to determine if there is utility in screening for pancreatic cancer in patients with diabetes to decrease the burden of pancreatic cancer in the US population.[Table: see text]
Predicting rapid progression and overall survival in stage II-III pancreatic cancer using a CT-based radiomic signature.
Authors: Xu Qinmei , Santos Toesca Diego Augusto , Schueler Emil , Jamalian Arash , Alkim Emel , Chang Daniel Tandel , Fisher George A. , Vitzthum Lucas , Gevaert Olivier , Itakura Haruka 
Published: January 2024

706 Background: We sought to assess the ability of a computed tomography (CT)-derived radiomic signature (RS) feature set to predict rapid tumor progression and overall survival (OS) in patients diagnosed with stage II-III pancreatic cancer undergoing stereotactic body radiation therapy (SBRT) in sequence with chemotherapy. Methods: We conducted a retrospective study on a cohort of 240 stage II-III pancreatic cancer patients who underwent SBRT in sequence with chemotherapy at a single institution (Stanford Hospital and Clinics). Among them, 83 had pre-SBRT contrast-enhanced CT images with segmented tumors, forming the imaging set, from which we extracted 900 radiomic (quantitative pixel-level imaging characteristic) features from delineated tumor regions-of-interest. For RS development, we divided the imaging set into a training set (n = 53) for model development and a test set (n = 30) for evaluation. We built a binary prediction model on the training set to identify patients at risk of rapid tumor progression within three months after SBRT. We utilized logistic regression with the Least Absolute Shrinkage and Selection Operator algorithm for feature selection and classification. To fine-tune parameters, we performed five-fold cross-validation on the training set, repeating each set of parameters five times. Finally, we assessed the model's performance on the test set (n = 30) using the area under the curve (AUC) value. We selected the model with the best AUC, while also generating the predictive radiomic feature set. For OS prognostication, we conducted both univariate and multivariate Cox proportional-hazards analyses using RS and clinical features (age, sex, stage, vessel involvement, tumor location, performance status, body mass index, biological equivalent dose of radiation) as potential predictors. Results: The enrolled cohort consisted of 127 men (mean age, 69 years ± 12 [SD]) and 113 women (mean age, 69 years ± 13 [SD]). Seventeen textural radiomic features were identified as the RS, which demonstrated a high AUC in the test set for the prediction of rapid progression (AUC 0.850; 95% CI: 0.725, 0.975). Age was associated with OS in the multivariate model while high RS (>0.5) was independently associated with OS in both univariate and multivariate models. Conclusions: CT-derived RS, combined with age, represent the most prognostic factors for stage II-III pancreatic cancer. RS, which likely reflects underlying biology or molecular alterations, contributes to the highest HR of poor OS and provide the strongest indicator of outcome following commonly used treatments in this patient population. [Table: see text]