bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of total tumor volume with 68Ga DOTATOC PET/CT in predicting response to 177-Lu-DOTATOC treatment in metastatic well-differentiated neuroendocrine tumors (NETs).
Authors: Vega-Zolano Elizabeth , Ruiz Erika , Caderillo-Ruiz German , Diaz Consuelo , Herrera Marytere , Torres Agredo Liliana Patricia , Soldevilla-Gallardo Irma , Michel-Sanchez Emiliano , Garcia-Perez Francisco Osvaldo 
Published: June 2023

e16248 Background: PET/CT with somatostatin analogues (68 Ga DOTATOC) is essential for decision-making prior to treatment with [177Lu–Dota0–Tyr3]–Octreotate (177Lu-DOTATOC), there are biological characteristics in this type of neoplasms that allow predicting the response to therapy, the tumor burden is one of the most important variables, however its estimation with conventional imaging tools is limited, currently there are reconstruction algorithms based on artificial intelligence that allow estimating the tumor burden using molecular imaging studies with 68 Ga DOTATOC, aim of this work is to determine the value of the total tumor load with this radiotracer as a predictor of overall survival in patients treated with 177Lu DOTATOC. Methods: 45 patients (11 men and 34 women) with an average age of 57.2 (range 47.2 to 66.5) with histopathological and immunohistochemical diagnosis of well-differentiated neuroendocrine tumors (NETs) in the period from 2015 to 2021 who received therapy with (177Lu-DOTATOC) and who had a baseline 68Ga DOTATOC PET to calculate total tumor volume (TVV) and semiquantitative uptake values were retrospectively included. Results: The mean follow-up was 29.3 +/- 6 months. Using ROC curves, a cut-off point of 100 cm3 was determined to differentiate responding and non-responding patients. The difference in the overall survival curves between both groups was statistically significant (470 days vs. 180 days) with p=0.07. The main sites of origin of the primary tumor were pancreas (n=24), lung (n=11), small intestine (n=7) and liver (n=3). The mean tumor volume was 305.8 cm3 (+/- 272). The organs with the highest uptake values were pancreas with SUVmax of 27.9 (range 10.1-42.4), rectum with SUVmax 26.5 (10.7-42.3) and liver with SUVmax of 22.1 (14.4-31.7), these uptake values did not have any type of relation to patient survival. Regarding therapy with 177 Lu DOTATOC, 8 received 14.8 Gbq (400mCi), 12; 22.2 GBq (600mCi) and 25; 29.6 GBq (800 mCi), no serious adverse effect or kidney function impairment was demonstrated after 177Lu DOTATOC therapy. No grade 3 or 4 haematological toxicity was identified. Conclusions: PET/CT with 68 Ga-DOTATOC is routinely used in the management of patients with neuroendocrine tumors and also allows categorizing patients according to their tumor volume to predict overall survival in patients treated with 177 Lu-DOTATOC, thus in such a way that it could be considered as an easily accessible and widely available prognostic imaging biomarker.
Treatment and outcomes of pancreatic cancer in Armenia: Hospital-based study.
Authors: Bardakhchyan Samvel , Mkhitaryan Sergo , Zohrabyan Davit , Safaryan Liana , Avagyan Armen , Harutyunyan Lilit , Arakelyan Jemma , Gharadaghyan Hovsep , Azizyan Sahak , Mailyan Mariam , Sargsyan Amalya , Harutyunyan Martin , Karapetyan Nune 
Published: June 2023

e16251 Background: Pancreatic cancer is one of the deadliest cancers in the world. In Armenia, pancreatic cancer is on the 12th place by incidence. The aim of this study is to evaluate treatment and outcomes of pancreatic cancer in Armenia during the last 12 years. Methods: For this retrospective hospital-based study we have collected data from three oncology centers in Armenia: “Muratsan” Hospital of Yerevan State Medical University, “Miqaelyan institute of surgery” and “Hematology center after prof. Yeolyan”. The information about patients with pancreatic cancer who were treated at these centers during 01/01/2010 - 01/01/2022 period was collected from the medical records. Log- rank test and Kaplan-Meier curves were used for survival analysis. Cox regression analysis was done for identification of main prognostic factors. Results: 70 patients with pancreatic cancer were involved in the final analysis. From them 44.3% were female. Median age at diagnosis was 63 years. Median follow up time was 10,5 months (range 2-146). 11,4% of patients had stage I-II, 27,1% stage III, 58,6% stage IV cancer. The main independent prognostic factor for overall survival (OS) was tumor grade, while TNM stage was not significant. 23% of patients were alive before study end date. Median OS was 12 months (range 2-146 months). Median overall survival was 35 months in stage I-II, 11 months in stage III and 11 months in stage IV. In stage I-III pancreatic cancer patients, those who had undergone surgery (44.4%) lived significantly longer (35 vs 11 months, p=0.011). 38.6% of patients received chemotherapy with Gemcitabine plus Capecitabine regimen, while 41.4% with FOLFIRINOX regimen. No significant difference in survival was found between these groups (11 vs 13 months, p=0.35). Conclusions: As our results has shown survival of pancreatic cancer patients in Armenia is dismal, not exceeding 1 year. Hopefully further research in the field and new treatment modalities will improve the situation.
Homologous recombination-related (HRR) gene mutation profiling and the association with TMB in Chinese patients with pancreatic cancer.
Authors: Wu Yin Bing , Yi Huan , Yu Yangyang , Xiao Mingzhe , Qi Chuang 
Published: June 2023

e16252 Background: Homologous recombination deficiency (HRD) is associated with tumorigenesis and could predict the response of PARP inhibitor (PARPi) therapy and immunotherapy. Loss of function or deleterious mutations in homologous recombination-related (HRR) genes contribute to HRD phenotype. Methods: Tumor tissue samples from 669 Chinese patients with pancreatic cancer were sequenced with 551 cancer-related genes. Based on the clinical evidence, 15 HRR genes ( ATM, BRCA1, BRCA2, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, RAD54L, PPP2R2A) were selected. 495 patients with WES data from the TCGA datasets were included for analysis. Results: In the Chinese cohort, 10.46% (70/669) patients exhibited somatic HRR (sHRR) gene mutations. ATM (4%) was the most common mutant gene, followed by BRCA2 (3%), BARD1 (1%), BRCA1 (1%), BRIP1 (1%), RAD51D (1%), CHEK2(1%). The germline HRR (gHRR) gene mutations were identified in 55.67% (118/245) patients. BRCA2 (23%) was the most common mutant gene, followed by ATM (10%), BRCA1 (9%), BRIP1 (9%), PALB2 (8%), BARD1 (7%), FANCL (3%). 1.49% (10/669) patients carried both germline and somatic HRR gene mutations. The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (3.97 vs 2.13, p<0.001). However, the median TMB was similar between the gHRR-Mut and the gHRR-WT patients (2.13 vs 2.13, p=0.49). In the TCGA cohort, 9.09% (45/495) patients exhibited sHRR gene mutations. The most common mutant gene was ATM (4%), followed by CDK12 (2%) BRCA2 (2%), BARD1 (1%). The sHRR-Mut patients had a higher median TMB compared to the sHRR-WT patients (1.03 vs 0.71, p<0.001). Totally, the somatic mutant frequency of HRR genes was similar between Chinese cohort and TCGA cohort (10.46% vs 9.09%, p = 0.113). For the TCGA cohort, the patients with sHRR-Mut had a similar median progression free survival compared to the ones with sHRR-WT (74.4 months vs not reached, p = 0.299). Conclusions: Our data reported the genetic landscape of HRR gene in Chinese pancreatic cancer patients. Patients with somatic HRR gene mutations had a significantly elevated TMB level. Our data suggest that patients with altered HRR genes may be rational candidates for precision oncology treatment and provide new opportunities to predict the tumor response to multiple treatments.
The efficacy of cationic amphiphilic antihistamines on outcomes of patients with pancreatic ductal adenocarcinoma.
Authors: Chiang Cho Han , Chiang Cho Hung , See Xin Ya , Hsia Yuanping , Chang Yu-Cheng , Wang Shih-Syuan , Chen Yuan-Jen , Chiang Cho Hsien , Peng Cheng-Ming , Shiah Her-Shyong 
Published: June 2023

e16253 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a poor prognosis. H1 antihistamines with cationic amphiphilic properties have been shown to possess antitumor effects and were associated with reduced mortality in several cancer types. We aimed to investigate the effects of cationic amphiphilic antihistamines on the outcomes of patients with PDAC. Methods: We conducted a retrospective cohort study at two tertiary centers in Taiwan between 2010 and 2021. We included all adult patients with histologically confirmed PDAC. Cationic amphiphilic antihistamines included desloratadine, cyproheptadine, and ebastine. The rest of the antihistamines were classified as non-cationic amphiphilic. Patients treated with cationic amphiphilic antihistamines were matched in a 1:2 ratio to patients treated with non-cationic amphiphilic antihistamines based on age, sex, and cancer stage. The primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS) and objective response rates (ORR). Results: Among 407 patients included in the study, 28 cationic amphiphilic antihistamine users were matched to 56 non-cationic amphiphilic antihistamine users. Over a median follow-up of 6.3 [IQR, 2.0-13.8] months, 67 patients died. Compared with non-users, patients who received cationic amphiphilic antihistamines had a longer OS (median 16.4 [IQR, 2.8 – 89.0] vs. 5.8 [IQR, 2.0 – 9.8] months; p < 0.001) and PFS (median 12.2 [IQR, 2.2 – 83.3] vs. 5.2 [IQR, 1.7 – 8.4] months; p = 0.002). In Cox proportional hazard models, the use of cationic amphiphilic antihistamines was associated with an approximately 60% lower risk of all-cause mortality and disease progression. Cationic amphiphilic antihistamine users also had greater ORR than non-users (complete or partial response, 39% vs. 7%, p = 0.004). Conclusions: The use of cationic amphiphilic antihistamines was associated with improved survival among patients with pancreatic cancer. [Table: see text]
Phase 1b study of batiraxcept (AVB-S6-500, BT) plus gemcitabine (G) and nab-paclitaxel (NP) as first-line treatment (1L) for advanced pancreatic adenocarcinoma (PDAC).
Authors: Sahai Vaibhav , Oberstein Paul Eliezer , Krishnamurthi Smitha S. , Gabrail Nashat Y. , Fountzilas Christos , Brenner Warren S. , Wainberg Zev A. , Yan Hongxia , McIntyre Gail , Lopez Charles D. , Mettu Niharika B. , Geller Robert B. 
Published: June 2023

e16258 Background: PDAC is a deadly aggressive cancer characterized by up to 80% tumor stroma enriched by macrophages, fibroblasts, and collagen deposition that influences resistance to therapy. Tyrosine kinase receptor AXL and ligand expression of growth arrest specific protein 6 (GAS6) produce tumor associated macrophages and fibroblasts and correlate with poor prognosis. GAS6 blockade partially reverses epithelial-to-mesenchymal transition of tumor and supports NK cell activation, inhibiting metastasis. As a novel decoy FC fusion protein, batiraxcept (BT) binds to GAS6 and demonstrates highly potent and specific AXL inhibition. Preclinical studies showed a relationship between AXL signaling and response to DNA damage in PDAC models. Methods: This dose escalation study tested BT 15 mg/kg on day 1 and 15 in combination with G 1000 mg/m2 and NP 125 mg/m2 days 1, 8, 15 of a 28-day cycle. Primary endpoints are safety and objective response rate (ORR) using RECIST v1.1; key secondary endpoints are progression free survival (PFS) and overall survival (OS); pharmacokinetic data were collected to determine exposure-PFS response (E-R) relationship. Results: As of January 17, 2023, 21 patients (pts) received BT/G/NP of which 10 (48%) were male and 3 (14%) received prior neoadjuvant/adjuvant therapy. BT-related AEs > 10% pts included fatigue (n=7, 33%), diarrhea (n=4, 19%), infusion related reaction and neutropenia (n=3, 14% each). Grade ≥ 3 BT-related AE occurred in 6 pts (29%). BT administration reduced GAS6 to non-quantifiable levels until treatment ended. 18 pts (86%) discontinued treatment, primarily due to toxicity (n=2) and progressive disease (n=13). Median (m) BT/G/NP treatment duration was 13.1 weeks (range 0.1─74.7). ORR is 29%; mPFS and mOS were 5.4 mo (2.1, 5.6) and 12.3 mo (4.11─NE) respectively. BT efficacy results are described by a minimally efficacious concentration (MEC) of 14.5 mg/L identified by E-R modeling. Conclusions: BT/G/NP combination was well tolerated, and the BT safety profile is consistent with prior trials. Patients with BT trough > MEC had longer PFS and OS. In addition, in these patients OS appears longer than historical data of 8.5 months. Due to increased stroma seen in PDAC, a higher BT MEC may be required to maximize efficacy. Higher BT dose levels in combination with G/NP are under study. Clinical trial information: NCT04983407 . [Table: see text]
Molecular and clinical characteristics of patients with KRAS mutated pancreatic ductal adenocarcinoma.
Authors: Xiao Alexander Hua , Desai Aakash , Halfdanarson Thorvardur Ragnar , Alberts Steven R , McWilliams Robert R. , Mahipal Amit , Bekaii-Saab Tanios S. , Shi Qian , Carr Ryan Michael , Ma Wen Wee 
Published: June 2023

e16259 Background: Patients with KRAS mutant (mt) pancreatic ductal adenocarcinoma (PADC) have worse survival outcomes compared to KRAS wild-type (wt) PDAC patients. However, the prognostic implication of the KRAS mutation subtype (e.g. G12D, G12R, G12V and Q61) remains unclear. Furthermore, the clinical and molecular characteristics associated with these mutation subtypes remain not well defined. Methods: A retrospective review was conducted on patients with KRAS PDAC who underwent Next Generation Sequencing at Mayo Clinic between December 1, 2018 and December 1, 2021. Their somatic mutations, RNA expression, demographics, disease characteristics, therapies offered, and clinical outcomes were collected via chart review. Results on KRAS wt were reported previously; KRAS mt are reported here. Results: A total of 158 KRAS mt patients (at diagnosis: average age 63.8 years, 57% male, 88 (56%) Stage IV) were included. 10% of patients had KRAS Q61 mutation, 14% G12R, 30% G12V and 46% G12D. G12R had a longer overall survival (OS) compared to the others (median 24.8 vs 17.5 months, unadjusted hazard ratio (HR) 0.68, p=0.05), particularly in patients with localized disease at diagnosis (median 35.4 vs 28.3 months, p=0.08). Among patients with metastatic disease at diagnosis, G12V had the lowest OS (median 9.8 vs 12.4 months, unadjusted HR 1.8, p=0.02). 137 (87%) patients had at least one pathogenic somatic variant, with statistically significant differences in SMAD4, TP53, MYC, RB1, KMT2D, RBM10, RNF43, KDM6A, KMT2C, RBM10, LRP1B, PIK3CA, and SMARC among the KRAS mt subtypes. 82 (52%) patients had at least one RNA expression variant, with statistically significant differences in CCND1, CCNE1, HRAS, MET, EGFR, and ERB3 among KRAS mt subtypes. Between these subtypes, there were no statistically significant differences in TMB value, location of PDAC or subsequent metastasis, lines of treatment (average 2.3), age at diagnosis, or gender. Conclusions: KRAS mt subtypes may confer different PDAC phenotypes. In our cohort, G12R is associated with improved OS while G12V correlates with worse prognosis in de novo metastatic disease. Additionally, there are differences in genomic variations and RNA expression between the KRAS mt subtypes. To further examine this, transcriptomic analysis is underway. [Table: see text]
Survival outcomes of liposomal irinotecan in patients with advanced pancreatic adenocarcinoma previously treated with conventional irinotecan-based chemotherapy: A single-institution experience.
Authors: Gupta Amol , Kamel Ihab R. , Laheru Dan 
Published: June 2023

e16260 Background: Gemcitabine-based and FOLFIRINOX (Oxaliplatin, irinotecan [IRI], 5-fluorouracil [5-FU], and leucovorin [LV]) regimens are common front-line therapies for patients with advanced pancreatic cancer (APC). Later-line options for these patients remain limited. Liposomal irinotecan (nal-IRI) plus 5-FU-LV has demonstrated a survival benefit in APC patients previously treated with gemcitabine-based treatment. However, the efficacy of nal-IRI plus 5-FU-LV in patients previously treated with conventional IRI containing regimens is controversial. Methods: A retrospective chart review was conducted on consecutive APC patients treated at our institution between November 2016 to January 2023 who completed at least one cycle of nal-IRI plus 5-FU-LV and were previously treated with conventional IRI. Data regarding survival outcomes were retrieved. The association between the survival outcomes and the interval between conventional IRI and nal-IRI was analyzed. Results: Forty-one patients met the inclusion criteria. One patient (2.4%) had a partial response (PR), and 12 patients (29.3%) had stable disease (SD) as their best response. The median overall duration of nal-IRI treatment was 2.2 (IQR: 1.4 – 5.2) months. The median progression-free survival (mPFS) was 1.9 (95% confidence interval [CI] 1.7 – 2.0) months, while the 6-month PFS rate was 24.4%. The median overall survival (mOS) was 5.9 (95% CI 3.5 – 8.2) months, and the 6-month OS rate was 48.7%. The median interval between the discontinuation of conventional IRI and starting nal-IRI was 6.5 (3.4 – 13.2) months. An interval between conventional IRI and nal-IRI ≥6.5 months was significantly associated with prolonged OS (8.5 [95% CI 5.9 - 11.1] versus 4.3 [95% CI 2.7 – 5.9] months; p = 0.017), but comparable PFS (2.0 [95% CI 1.0 – 2.8] versus 1.7 [95% CI 1.5 – 1.9] months; p = 0.052). Conclusions: Patients previously treated with conventional IRI containing regimens appear to still benefit from nal-IRI plus 5-FU-LV. A longer interval between conventional IRI and nal-IRI was associated with better OS. A sequence strategy introducing a nal-IRI-based regimen at later lines may be feasible in selected APC patients previously treated with conventional IRI, given the limited therapeutic options. Further prospective studies are warranted. [Table: see text]
Single-cell RNA sequencing and influences of necroptosis-associated myeloid lineages in immune microenvironment of PDAC.
Authors: Dong Weiwei , Zhao Huixia , Zhang He , Zeng Zhiyan , Hu Yanyan , Fan Tongqiang , Zheng Liuqing , Wang Qian , Xiao Shanshan , Wang Tao , Xiao Wenhua 
Published: June 2023

e16261 Background: Tumor-infiltrating myeloid cells (TIMs) are abundant in tumor stroma and emerging evidence indicate that the presence of these cells influences clinical outcomes in many cancer types. TIMs play important roles in tumor progression and specific subsets may exhibit divergent anti-tumor or tumor-promoting functions. Currently, the molecular characteristics of TIMs in pancreatic ductal adenocarcinoma (PDAC) largely remain unknown. Like other programmed cell death procedures such as ferroptosis and pyroptosis, necroptosis has recently emerged as an important cellular event that modulates tumorigenesis and tumor progression. Combination of necroptosis and TIMs is of great interest to study the molecular mechanism of clinical outcomes for PDAC patients. Methods: This study enrolled 16 PDAC patients. The scRNA-seq data were obtained from a published dataset and each patient included primary tumor, metastatic tumor, primary tumor-adjacent and PBMC samples. All myeloid cells comprising granulocytes, monocytes, macrophages, and dendritic cells from enrolled patients were extracted for further analysis. We performed comprehensive analysis about the characteristics of myeloid lineages, differentially expressed genes, pathway enrichment analysis and novel cell subtype identification. The necroptosis-associated novel TIMs cell sub-clusters were elucidated in detail. Results: To comprehensively analyze the heterogeneous TIMs microenvironment in PDAC patients using scRNA-seq dataset, we firstly obtained consistently upregulated genes among granulocytes, monocytes, macrophages, and dendritic cell types between tumor samples and non-tumor samples. Those uniquely expressed genes represent different functions in necroptosis-associated TIMs cells. In total, we identified 10 necroptosis-associated upregulated genes in PDAC tumors and 5 upregulated genes in tumor-adjacent and peripheral blood samples, respectively. Based on the cells expressed those necroptosis-related genes, we identified three novel cell populations, including GLUL-SQSTM1- RTM, HSP90AA1+HSP90AB1+ mast cells, and JAK3+TLR4+ CD16 monocytes, which were regulators of immunity either tumor-promoters or tumor-suppressors. Clinical outcomes further supported their function roles in the PDAC tumor microenvironment. Conclusions: This study comprehensively studied the heterogeneity of myeloid microenvironment in PDAC by scRNA-Seq. Several necroptosis-associated genes and myeloid cell sub-clusters were identified and they have prognostic clinical values in PDAC. These preliminary results were helpful for further understanding the molecular mechanism of PDAC treatment strategies.
NALIRIFOX vs FOLFIRINOX vs gemcitabine plus nab-paclitaxel as first-line treatment of advanced pancreatic cancer: An individual patient data pooled analysis of phase 3 registration trials.
Authors: Nichetti Federico , Rota Simone , Gusmaroli Eleonora , Pircher Chiara Carlotta , Franza Andrea , De Braud Filippo G. , Di Bartolomeo Maria , Niger Monica 
Published: June 2023

e16262 Background: The NAPOLI-3 trial showed the superiority of the NALIRIFOX regimen over the combination of gemcitabine and nab-Paclitaxel (GemNabP) as first-line treatment (1LTx) of advanced pancreatic cancer (PDAC), thus being candidate as a reference regimen in this setting. However, a comparison with the FOLFIRINOX regimen has not yet been performed. Methods: We performed a pooled analysis of phase III trials that defined FOLFIRINOX, NALIRIFOX and GemNabP as optimal 1LTx options in advanced PDAC. Individual patient outcomes were retrieved from Kaplan Meier plots of each trial, and analysed after assessment of data reconstruction accuracy. Progression free survival (PFS) and overall survival (OS) were compared between the three different arms, using Cox proportional hazard models including each trial as a random effect variable to account for inter-trial variability. Overall response rates (ORR) and Grade 3 or 4 (G3/4) toxicity rates were also compared. Results: A total of 1372 patients treated with FOLFIRINOX (n=171, 12), NALIRIFOX (n=383, 28) and GemNabP (n=818, 60) were included. Median PFS was significantly longer in patients treated with NALIRIFOX (7.4 months) as compared to FOLFIRINOX [6.4 months, HR 1.48 (95% CI 1.21 - 1.82), p<.001] and GemNabP [5.6 months, HR 1.45 (95% CI 1.24 - 1.70), p = p<.001]. NALIRIFOX also provided significantly higher ORR [42% vs 32% (FOLFIRINOX) vs 29% (GemNabP), p<.001]. GemNabP was associated with poorer OS [9.2 months, HR 1.25 (95% CI 1.07 - 1.46), p=0.005], while no significant difference was observed between FOLFIRINOX [11.1 months, HR 1.12, (95% CI 0.88 - 1.43), p=0.344] and NALIRIFOX (11.1 months). Among G3/4 events, NALIRIFOX was associated with higher rates of diarrhea [p<.001] and lower rates of peripheral neuropathy, thrombocytopenia and neutropenia [p<.001], though with no difference in febrile neutropenia occurrence [p=0.158]. Conclusions: NALIRIFOX may provide superior ORR and PFS as compared to FOLFIRINOX and GemNabP as 1LTx of advanced PDAC, though with higher gastrointestinal toxicities and no difference in OS compared to FOLFIRINOX. Careful patient selection, drug costs consideration and direct comparison between FOLFIRINOX and NALIRIFOX is warranted. [Table: see text]