bluuebunny/crossref_metadata_2025_split huggingface dataset:
Short-term and long-term outcomes of transduodenal ampullectomy for patients with early ampullary cancer.
Authors: Miyamoto Ryoichi 
Published: July 2024

e16244 Background: Transduodenal ampullectomy (TDA) has been attempted in early ampullary cancer. However, the indication and extent of TDA with curative intent remain controversial. Here, we address the perioperative and long-term outcomes of patients with early ampullary cancer who underwent TDA. Methods: Ten early ampullary cancer patients who underwent TDA and 11 early ampullary cancer patients who underwent subtotal stomach-preserving pancreatoduodenectomy (SSPPD) at this institute were respectively enrolled. Among this cohort, we analyzed the perioperative outcomes and long-term outcomes. Results: In terms of the perioperative outcomes between the TDA and SSPPD groups, the TDA group exhibited a shorter operating time (244 minutes vs. 390 minutes, p = 0.003), less intraoperative blood loss (67.5 grams vs. 774 grams, p = 0.006) and shorter length of postoperative hospital stay (15 days vs. 33 days). With respect to the postoperative nutrition status, the TDA group exhibited less postoperative weight loss (0.67% vs. 8.95%, p = 0.021), a better CONUT score (1.0 vs. 2.1, p = 0.011) and a better PNI score (42.9 vs. 40.9, p = 0.018). The 5-year survival rate in the adenoma with high-grade dysplasia (HGD) and T1a (M) groups was 100%, while the median survival time in the T1a (OD) group was 20.7 months (p = 0.0028). Conclusions: TDA is assumed to be a feasible and effective surgical procedure for the treatment of selected patients with early ampullary cancer, including patients with adenoma with HGD or T1a (M) ampullary cancer.
Peritumoral HLJ1-STAT3 pathway investigation in carcinogen-induced hepatocellular carcinoma.
Authors: Luo Wei-Jia , Chien Min-Hui , Yu Sung-Liang , Yang Pan-Chyr , Su Kang-Yi 
Published: July 2024

e16251 Background: Hepatocellular carcinoma (HCC) is a major global health issue and its treatment options have been limited. Therefore, it is urgent to develop cancer biomarkers for defining cancer risk, diagnosis, prognosis, and even finding new therapeutic targets. Human Liver DnaJ-Like Protein (HLJ1), which belongs to DnaJ heat shock protein family (HSP40) member B4 (DNAJB4), has been identified as a tumor suppressor in various cancers including lung cancer and colorectal cancer. Though the biological function of HLJ1 in either cancer or the liver has emerged in recent years, the precise role of HLJ1 in HCC carcinogenesis is still unclear. Methods: Samples for gene expression cDNA microarray were from 6-8 weeks wild-type (WT) and HLJ1 knockout (HLJ1-/-) mice liver. For the long-term carcinogenesis study, both mice are injected with 20 mg/kgbw diethylnitrosamine (DEN) at postnatal day 15. After that, 50 mg/kgbw DEN was administrated weekly to mice between the ages of 4 to 12 weeks. Mice were sacrificed at ages 30 and 36 weeks to assess the tumor count and size. For the short-term DEN study, 6-8-week-old mice were injected with 100 mg/kg DEN, and 24 and 48 hours after administration the liver tissues were frozen and fixed for western blotting and IHC analysis. Cancer cell transplantation was performed by intrasplenic injection of HLJ1-wildtype LLC and B16F1 cells into both genotypes. Clinical information of 362 liver cancer patients from the TCGA database was analyzed for the correlation between HLJ1 expression and survival. Results: In cDNA microarray analysis, We demonstrated that HLJ1 deficiency led to HCC gene signatures associated with activated IL-6/STAT3 signaling pathways. We used the DEN as a carcinogen and found STAT3 and H2AX phosphorylation induced by short-term DEN treatment was amplified in HLJ1-deficient mice. In long-term DEN experiments, HLJ1 deletion promoted tumor initiation and proliferation at the early and late stages of HCC progression accompanied by pronounced STAT3 phosphorylation in the normal part instead of the tumor part. Furthermore, transplantation of HLJ1-wildtype B16F1 and LLC cell lines into HLJ1-deficient mice led to more tumorigenic phenotype than into wildtype mice. Clinical information of 362 liver cancer patients from the TCGA database exhibited that higher expression of HLJ1 in the tumor part is correlated to a lower disease-specific survival rate. Conclusions: In summary, HLJ1 protects against DEN-induced HCC hepatocarcinogenesis through the regulation of STAT3 signaling in the peritumoral normal cells. Hence, HLJ1 can be a prognostic biomarker for liver cancer and a promising therapeutic target for HCC in the future.
Surgical resection versus thermal ablation: Comparison of sequential options after successful TACE downstaging therapy for unresectable hepatocellular carcinoma—A long-term multi-institutional study.
Authors: An Chao , Wu Pei-Hong , Huang Jin-Hua 
Published: July 2024

e16258 Background: Transarterial chemoembolization (TACE) is an effective and safe treatment for unresectable hepatocellular carcinoma (uHCC). However, the selection of sequential therapeutic modalities after TACE downstaging therapy is still controversial. The aim of this study is to compare the efficacy and safety of surgical resection (SR) and thermal ablation (TA) after successful TACE downstaging therapy for uHCC. Methods: In this real-world multi-institutional study from June 2008 to October 2022, 8,219 consecutive patients with HCC underwent conventional TACE at 12 hospitals. Patients underwent successful TACE downstaging therapy for uHCC beyond Milan criteria, who were assigned into SR group and TA group. The propensity score matching (PSM) was applied to reduce selection bias between groups. Cumulative overall survival (OS) and progression-free survival (PFS) were compared using the Kaplan‒Meier method with the log-rank test. A comparison analysis of major complications was performed using the c2 test. Results: 609 (7.4%) patients received SR or TA after TACE. After PSM 1:1, 185 patients in the SR group were matched with 185 in the TA group. After 4.5 years of median follow-up time, the cumulative 1-, 3-, 5- and 10-year OS rates were 98.8%, 89.3%, 82.9% and 64.4% in the SR group and 99.5%, 88.4%, 75.3% and 53.9% in the TA group, respectively, showing no significant difference ( P = .381). The cumulative 1-, 3-, 5- and 10-year PFS rates were 88.5%, 69.2%, 58.8% and 32.2% in the SR group and 90.6%, 71.4%, 53.1% and 32.0% in the TA group, respectively, showing no significant difference ( P = .855). The incidences of major complications were 6.5% in the SR group and 7.6% in the TA group, showing no significant difference ( P = .684). Conclusions: For uHCC patients beyond the Milan criteria received TACE downstaging therapy, TA might be acceptable as an alternative to SR in first-line sequential treatment scheme.
Second-line (2L) treatment patterns and clinical outcomes among real-world (RW) patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with FOLFIRINOX (FFX) or gemcitabine + nab-paclitaxel (GnP) in the first-line (1L).
Authors: Paluri Ravi Kumar , Silver Michelle , Cockrum Paul , Dennen Syvart 
Published: July 2024

e16322 Background: FFX and GnP are the most common 1L treatments for pts with mPDAC. Approximately half of pts treated with these regimens continue to 2L, though optimal 2L treatment is unclear. We identified a RW sample of mPDAC pts treated with 1L FFX or GnP and assessed their 2L treatment patterns, duration of therapy (DoT), overall survival (OS), and time to next treatment (TTNT). Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2021 who initiated 1L treatment with FFX or GnP ≤90 days from metastatic diagnosis date were included. To observe 2L treatment patterns, pts were required to have ≥1 year of follow-up unless death occurred first. Pts were censored at date of last activity absent death. Kaplan-Meier analyses were used to assess the median OS and TTNT from the start of 1L. Pts were grouped into five treatment categories: 1L FFX-only, 1L FFX + 2L GnP, 1L FFX + 2L other, 1L GnP-only, and 1L GnP + any 2L. Pts with 2L treatments were not restricted by whether they received 3L therapy or later. Results: 936 1L GnP and 712 1L FFX pts met the study inclusion criteria. 572 (61%) 1L GnP pts received 1L GnP-only and 364 (39%) received 1L GnP + any 2L (“any 2L” included 78 Nal-IRI, 59 FOLFOX, 57 FFX pts, and 170 pts with various combinations of chemotherapies and/or targeted therapies, with < 50 pts per regimen). 300 (42%) 1L FFX pts received 1L FFX-only, 287 (40%) received 1L FFX + 2L GnP, and 125 (18%) received 1L FFX + 2L other (“2L other” included 35 capecitabine monotherapy pts, 27 G monotherapy pts, all other regimens < 20 pts). Pts with 1L FFX were younger, slightly more likely to be male, and had slightly better ECOG scores than 1L GnP pts. Median 1L DoT was shorter for 1L-only pts compared to pts with 2L therapies. Median OS was shortest for 1L-only pts and longest for 1L FFX + 2L other. Median OS was similar for 1L FFX + 2L GnP and 1L GnP + any 2L. Median TTNT was similar across treatment categories with a 2L. Conclusions: In a RW sample of mPDAC pts, those with 1L-only had poor survival. Pts with 1L FFX + 2L GnP had a similar survival to 1L GnP + any 2L. [Table: see text]
Interaction of BRCA1 vs BRCA2 pathogenic variants with primary tumor location in pancreatic cancer.
Authors: Hood Ryan , Seewald Nicholas J. , Rathore Srishti , Reiss Kim Anna 
Published: July 2024

e16326 Background: BRCA1/2 germline or somatic pathogenic variants (PVs) are found in 5-10% of pancreatic adenocarcinoma (PDAC) patients. Recent data suggest that BRCA2 PVs may be associated with increased overall survival (OS) compared to BRCA1 PVs after adjusting for treatment and clinical characteristics. Additionally, pancreatic tail PDAC was found to harbor PVs in BRCA1/2 more frequently compared to PDAC within the pancreatic head (HOP). We hypothesized that tumor location in patients with BRCA1 and BRCA2 PVs would associate with overall survival and somatic mutation profile. Methods: We conducted a retrospective cohort study using a database of patients with PDAC and BRCA1/2 PVs at an academic center. Demographic and clinical data were compared by Fisher’s exact test. OS was measured using date of death or last follow-up and compared by Cox proportional hazards regression adjusting for treatment with platinum-based chemotherapy and curative-intent surgical resection. Cases with available next generation somatic sequencing were reviewed. Results: There were no significant differences in age, sex, stage at diagnosis, ECOG status at diagnosis, tumor location, treatments, or sites of metastasis between patients with BRCA1 vs BRCA2 PVs. In the overall cohort, we observed no significant difference in OS between patients with BRCA1 vs BRCA2 (17.0 vs 20.2 months). However, survival analysis stratified by tumor location demonstrated that BRCA1 patients with HOP tumors had significantly worse OS compared to BRCA2 patients with HOP tumors (13.1 vs 25.7 months, p = 0.014) and had a significantly higher rate of TP53 mutations (100% vs 50%, p = 0.032). No significant differences in OS or rates of TP53 mutations were observed in the body/tail of the pancreas. Conclusions: These results suggest that there may be differences in rates of somatic variants between BRCA1- and BRCA2-related HOP PDAC and suggest an interaction between BRCA1/2 tumor biology and anatomical location. [Table: see text]
Nab-paclitaxel and gemcitabine (modified) in combination with oral cobimetinib and encorafenib following FOLFIRINOX in patients with metastatic G12D and G12V pancreatic cancer.
Authors: Ardalan Bach , Azqueta Jose Ignacio , England Jonathan , Sleeman Danny , Gonzalez Rosali 
Published: July 2024

e16330 Background: Pancreatic cancer is the only human cancer in which most of the tumors are KRAS mutated. A majority of the mutations occur in codon 12. Mutations percentages are as follows: G12D (50%), G12V (35%) and G12R(12%). We are reporting on a pilot study in patients with advanced pancreatic cancer who have failed, or have become resistant to FOLFIRINOX. Thereafter the patients were placed on Nab-paclitaxel and Gemcitabine in combination with oral Cobimetinib and encorafenib. Methods: Patients with advanced pancreatic cancers are typically offered modified FOLFIRINOX followed by Nab-paclitaxel and Gemcitabine. After obtaining a written informed consent, we conducted a single arm study of patients with pathologic proven unresectable metastatic pancreatic cancer. Patients who had failed FOLFRINOX were placed on a modified regimen of Gemcitabine (1000mg/m2) and Nab-paclitaxel (125 mg/M2) on days 1 and 15 every 28-day cycle. Oral medications, Cobimetinib 20 mg bid and encorafenib of 150 mg bid were given. The oral chemotherapies were administered weekdays only during the 28-day cycle. The primary end point was to determine the response rate from the time the patients were placed on Nab-paclitaxel and Gemcitabine and the oral medication. The secondary endpoint was to assess the overall survivorship from the beginning of the therapy, and overall toxicities of the combination therapy. Twelve patients with advanced metastatic pancreatic cancer were enrolled on this pilot study. Six patients were male, and the median age was 67 years. Liver metastases were present in eight patients. Treatment was continued as long as there was no disease progression. CBC, CMP, CA19-9 was performed every other week. CT and PET scan was ordered every eight weeks. Results: Overall follow up is from 5 to 19 months (median 14 months). Segmental median survival from the start of oral therapy in conjunction with Nab-paclitaxel and Gemcitabine is 5 months (2-9 months). As from now,all patients are alive and 10 of 12 patients are on therapy. One patient who achieved pathologic response in the liver was deemed operable, and pathologically the distal pancreatectomy demonstrated NO disease. The other patient has progressed and is not on treatment. Grade 3 non-hematological toxicities included nausea, vomiting and fatigue in 3 of 12 patients. Hematological toxicities included neutropenia and neutrophil support was needed in 6 out of 12 patients. Median survivorship has NOT been reached. In this small study, we have observed a rapid and dramatic reduction in tumor volume. Conclusions: The combination of MEK and BRAF inhibitors with chemotherapy may be potentially active in pancreatic tumors (G12D and G12V). Based on the data presented, Nab-paclitaxel and Gemcitabine in combination with oral Cobimetinib and encorafenib needs to be further explored in a larger cohort of patients.
TisCRT-LAPC: A phase II study of tislelizumab combined with nab-paclitaxel and gemcitabine (AG) followed by consolidative radiotherapy in locally advanced pancreatic cancer (LAPC).
Authors: Guo Xi , Zhou Yuhong , Ji Yuan , Lou Wenhui , Wu Lili , Wang Wenquan 
Published: July 2024

e16350 Background: We have previously reported that consolidative chemoradiotherapy following induced chemotherapy is an optimal regimen for LAPC. This study aimed to evaluate the clinical benefit of tislelizumab (anti-PD-1) plus AG chemotherapy sequenced by consolidative radiotherapy for therapy-naive LAPC. Methods: Patients (pts) with LAPC were enrolled and received tislelizumab (TIS) 200mg Q3W, nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 on days 1 and 8 every three weeks for 6 cycles. Those who did not progressed continued to receive radiotherapy and tislelizumab. After that, tislelizumab and gemcitabine were ongoing until progression. The primary endpoint was 12-month progression-free survival rate, and secondary endpoints included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety and biomarker explore. Results: From April 2021 to December 2023, 30 pts were enrolled, 29 pts completed at least one efficacy assessment, 1 dropped out due to jaundice on liver damage for more than 6 weeks without medication. 17 males and 13 females with a median age of 58.5 years. 12.5% (3/24) progressed after TIS+AG treatment and did not receive radiotherapy, 87.5% (21/24) had completed radiotherapy and 5 pts were still receiving TIS+AG treatment. ORR was 31.0%, and DCR was 96.6%, respectively. The median follow-up time was 14.0 months, and the median PFS was 11.2 months (95%CI,7.6-26.6). The median OS was not reached. 6-month and 12-month PFS rates were 84.2% and 44.3%, respectively. Most patients (27/30) showed serum CA19-9 decline with different degrees.The most common treatment-emergent adverse events (TEAEs) were myelosuppression, rash, and fatigue. Grade 3/4 TEAEs were neutropenia in 5 patients, anemia in 1 patient, and rash in 1 patient. Immune-related AEs included 1 Grade-1 myocarditis, 1 Grade-1 pneumonia and 1 Grade-3 disfunction of liver. Conclusions: This study demonstrates the effectiveness and manageable safety of tislelizumab combined with AG chemotherapy sequenced by radiotherapy for LAPC. Exploratory analysis of correlative biomarkers suggests that KRAS ctDNA negative at baseline may be a pedictive markers benefit with treatments. Clinical trial information: ChiCTR2000040872.
Impact of personalized peptide neoantigen vaccines on immunologic responses in patients with pancreatic cancer.
Authors: Hu Landian , Zhang Yuchao , Kong Xiangyin , Wu Zhenchuan , Wang Hailong 
Published: July 2024

e16351 Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that often resists conventional therapies. One of the most promising alternative treatments is personalized neoantigen vaccines that target specific mutations in each patient’s tumor. These vaccines aim to activate the immune system to fight cancer cells. However, how this type of vaccine affects immune cells across different vaccination phases is poorly understood. Methods: Here we report the safety and dynamic immunological responses of peptide-based vaccines after chemotherapy in patients with resected PDAC in a single-center open-label phase 1b trial (registered at ClinicalTrials.gov [NCT03558945]). The primary endpoint was safety, assessed by the incidence of adverse events in all vaccinated patients. The key secondary endpoints included prognosis assessed by recurrence-free survival and overall survival rate. Results: We observed only 3 grade ≥3 adverse events in 2 patients (12.5%) and no grade ≥4 events. Vaccinated patients achieved favorable survival outcomes, with a 3-year recurrence-free survival rate of 56% and a 3-year overall survival rate of 74%. Using single-cell sequencing, we revealed the dynamics of vaccine-induced immune responses, with CD8+ cytotoxic T cells expanding at the priming phase and CD4+ T cells at the boosting phase. The CD8+ cytotoxic T cells had a higher proportion (average, 38.4%) of persistent expansion than the CD4+ T cells (average, 3.7%), with a range of 2.8~21.8 months duration. We also discovered a helper B-cell subtype that interacted with T cells and was associated with prognosis, suggesting a role for B-cell epitopes in vaccine effectiveness. Conclusions: These results provide valuable insights for optimizing peptide-based neoantigen vaccine design, regimen, and evaluation strategies. Clinical trial information: NCT03558945 .
Unfolding the role of cell state on stress granule heterogeneity and function in pancreatic cancer.
Authors: Redding Alexandra 
Published: July 2024

e16357 Background: A major impediment to cancer therapy is the reality that cancer is a heterogeneous disease. A single tumor can consist of many genotypic or phenotypic profiles, which are marked by degrees of sensitivity to different therapeutics. Identifying and targeting origins of cancer cell heterogeneity is critical for predicting patient outcome and enhancing treatment efficacy. We observe a novel source of cancer cell heterogeneity that involves one of the largest stress-sensing platforms described to date: the stress granule (SG). Stress granules are non-membranous, cytoplasmic organelles that assemble in response to stress, and promote cell survival. Deregulation of SGs has been linked to several pathological conditions, including cancer, neurodegeneration, ischemia, and viral infections. SGs have been shown to promote tumor growth and metastasis, as well as contribute to mechanisms of chemo-resistance. Thus, these signaling hubs are emerging as a potential target in cancer. Methods: To induce SG formation, human pancreatic ductal adenocarcinoma (PDAC) cell lines were treated with sodium arsenite, thapsigargin, or exposed to hypoxic conditions. Immunoflourescent staining of core SG proteins was then conducted. To investigate cell cycle-driven mechanisms of SG heterogeneity, cell cycle stage was identified by expression of a Fluorescent ubiquitination-based cell cycle indicator (Fucci) lentiviral system. To investigate cPLA2’s role in SG formation, the chemical inhibitor Pyrrophenone, an shRNA targeting cPLA2, and an exogenous full-length or cleaved form of cPLA2, were used. In vivo, ES149 cells expressing Luciferase and the Fucci system were orthotopically implanted into C57BL/6 mice. Established tumors were treated every 3 days with Vehicle, Oxaliplatin, Pyrrophenone, or a combination of the latter. Tumor size was tracked via IVIS Spectrum. Fucci flourescence was used to identify cell cycle phase. SGs and cell death were assessed by immunoflourescent staining of tumors. Results: Cancer cells show a high degree of heterogeneity in their production of SGs. Cell cycle phase dictates SG heterogeneity. G2 phase cells have significantly higher levels of SG formation as compared cells in G1/S. This process is regulated by cleavage of the cPLA2 protein. Oxaliplatin administration increases G2 phase content in tumors. Co-treatment with Oxaliplatin and Pyrrophenone significantly decreases SG formation, increases cell death, and leads to tumor regressions in vivo. Conclusions: G2 phase cancer cells develop higher levels of SGs when exposed to stressful stimuli, as compared to G1/S phase counterparts. The cPLA2 protein is cleaved into a catalytically dead form that is present in G1/S phases, but absent in G2 phase. Oxaliplatin treatment in vivo leads to an increase in G2 phase tumor cells. When paired with cPLA2 inhibition, this results in increased cancer cell death and decreased tumor growth.