bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimal preoperative multidisciplinary treatment in borderline resectable pancreatic cancer: Results of a dual-center study.
Authors: Kimura Nana , Yamada Suguru , Takami Hideki , Murotani Kenta , Yoshioka Isaku , Shibuya Kazuto , Sonohara Fuminori , Hoshino Yui , Hirano Katsuhisa , Watanabe Toru , Baba Hayato , Mori Kosuke , Miwa Takeshi , Tanaka Haruyoshi , Kanda Mitsuro , Hayashi Masamichi , Matsui Koshi , Okumura Tomoyuki , Kodera Yasuhiro , Fujii Tsutomu 
Published: January 2022

530 Background: For borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC), upfront surgery was standard in the past, and the usefulness of neoadjuvant treatment (NAT) has been reported in recent years. However, few studies have been conducted to date on whether there is a difference in optimal treatment between BR-PDAC invading the portal vein (BR-PV) or abutting major arteries (BR-A). The objective of this study was to investigate the optimal treatment for BR-PV and BR-A. Methods: We retrospectively analyzed 199 patients with BR-PDAC (88 BR-PV and 111 BR-A). For each BR-PV and BR-A, we analyzed the following points. 1) Comparison of prognosis of upfront surgery vs. NAT, 2) Comparison of regimens in patients who underwent NAT, 3) Prognostic factors in patients who underwent resection after NAT. Results: 1) In BR-PV patients who underwent upfront surgery (n = 46)/NAT (n = 42), survival was significantly better in the NAT group (3-year overall survival (OS): 5.8%/35.5%, p = 0.004). In BR-A patients who underwent upfront surgery (n = 48)/NAT (n = 63), survival was also significantly better in the NAT group (3-year OS:15.5%/41.7%, p < 0.001). 2) The prognosis tended to be better in patients who received newer chemotherapeutic regimens, such as FOLFIRINOX and gemcitabine with nab-paclitaxel than older regimens such as gemcitabine and/or S-1, in each BR-PV and BR-A patients. The R0 rate was significantly higher (100%) when radiotherapy was used in combination with chemotherapy, regardless of the chemotherapeutic regimen. 3) In 36 BR-PV patients who underwent surgery after NAT, univariate analysis revealed that normalization of tumor marker levels ( p = 0.028) and preoperative high prognostic nutritional index (PNI) ( p = 0.022) were significantly associated with a favorable prognosis. In 39 BR-A patients who underwent surgery after NAT, multivariate analysis revealed that preoperative PNI > 42.5 was an independent prognostic factor (hazard ratio: 0.15, p = 0.014). The length of NAT was not a prognostic factor for either BR-PV or BR-A. Conclusions: NAT using newer chemotherapy is essential for improving the prognosis of BR pancreatic cancer. These findings suggest that prognosis may be improved by maintaining good nutritional status during preoperative treatment, not by the length of preoperative treatment. In addition, surgery after normalization of tumor markers levels by preoperative treatment contributes to the prolongation of survival.
Health outcomes of gBRCA testing strategies for metastatic pancreatic cancer patients.
Authors: Fan Lin , Agnihotri Neeharika , Ambavane Apoorva , Li Weiyan , Joo Seongjung , Yoo Hyun Kyoo , Muston Dominic 
Published: January 2022

537 Background: About 4-8% metastatic pancreatic cancer (mPC) patients have germline BRCA mutation (gBRCAm). Identifying gBRCAm through early testing benefits mPC patients through: 1. better health outcomes when gBRCAm patients receive platinum (plat) based 1st line (1L) chemotherapy compared to non-plat 1L regimen; 2. additional benefit, if eligible, from olaparib (O) maintenance treatment (mTx), which was approved by the FDA for the gBRCAm mPC patients who have not progressed on at least 16 weeks of a 1L plat regimen. Objective: To evaluate the health outcomes of gBRCA testing and treatment strategies among mPC patients using simulation model. Methods: A 3-state partitioned survival model was developed to assess the lifetime (20 year) health outcomes among treatment naïve mPC patients for the following strategies: 1. No gBRCA testing, no O mTx; 2. gBRCA testing before 1L, no O mTx; 3. gBRCA testing before 1L, O mTx; 4. gBRCA testing after 1L, O mTx. Without gBRCAm information before 1L (i.e., strategy 1&4) or if gBRCA negative, 45% mPC patients with good performance status (PS) and 27% with poor PS received 1L plat. We assumed that for gBRCAm patients, if known, 90% with good PS and 50% with poor PS received 1st line plat (i.e., strategy 2&3) in the base case. We assumed gBRCA testing had 100% of sensitivity and specificity. OS and PFS survival curves were extrapolated from pivotal trials. The additional health outcome benefit from O mTx after 16 weeks were modeled using efficacy from POLO trial. Health outcomes were measured by life years (LY) and, after applying health utilities by health state, quality adjusted life years (QALY). Results: The proportion of gBRCAm mPC patients receiving O mTx were 58.7% (4.4% of mPC patients) for strategy 3 vs 30.0% (2.2% of mPC patients) for strategy 4. For gBRCAm mPC patients, no testing generated the least LY and QALY, while testing before 1st line with O mTx resulted in the most. This trend was also observed in the overall cohort of mPC patients with the best outcomes from testing before 1st line with O mTx and worse outcomes from no testing or testing after 1st line with O Mtx. These survival gains are primarily derived by higher proportion of patients on platinum with better survival along with O Mtx gains. Conclusions: mPC patients achieve the highest health benefits by gBRCA testing before 1L treatment followed by O mTx, even with less than 5% mPC patients becoming eligible for O mTx (strategy 3).[Table: see text]
A phase II study of nivolumab in combination with modified FOLFIRINOX for metastatic pancreatic cancer.
Authors: Ueno Makoto , Morizane Chigusa , Ikeda Masafumi , Sudo Kentaro , Hirashima Yoshinori , Kuroda Masataka , Fukuyama Yuki , Okusaka Takuji , Furuse Junji 
Published: January 2022

553 Background: Although FOLFIRINOX and nab-paclitaxel plus gemcitabine have improved the survival of unresectable pancreatic cancer patients, high unmet medical needs still exist for the treatment of this cancer. Nivolumab has shown efficacy for multiple cancer types in not only its monotherapy but also combinations with conventional chemotherapies. This study aimed to assess the efficacy and safety of nivolumab in combination with modified FOLFIRINOX, which is one of the first line chemotherapy for pancreatic cancer. Methods: Thirty-one treatment-naïve patients with metastatic, unresectable/recurrent pancreatic cancer patients received nivolumab (480 mg, every 4 weeks) plus modified FOLFIRINOX (oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, irinotecan 150 mg/m2 and fluorouracil 2400 mg/m2, every 2 weeks). The primary endpoint was objective response rate (ORR) (central assessment). Secondary endpoints were overall survival (OS), progression-free survival (PFS) (central assessment), safety etc. Results: The median duration of follow-up was 13.40 months. ORR was 32.3% (CR: 0.0%, PR: 32.3%) and the median duration of response was 7.36 (range 3.5-20.1+) months. Median OS and PFS were 13.40 (90% CI 10.87-15.24) months and 7.39 (90% CI 3.88-7.59) months, respectively. The 1-year survival rate was 54.8 (90% CI 39.1-68.1) %. The most frequently reported grade 3-4 drug-related adverse events were neutrophil count decreased (38.7%), decreased appetite (16.1%), hypokalemia (12.9%), febrile neutropenia (9.7%), nausea (9.7%) and white blood cell count decreased (9.7%). Adrenal insufficiency (3.2%) was observed as immune mediated adverse event. Conclusions: Nivolumab in combination with modified FOLFIRINOX had a manageable safety profile in patients with metastatic pancreatic cancer. Additional work is needed to determine the population who can benefit from the combination. Clinical trial information: JapicCTI-184230.
Preliminary results of a phase 1 study of sea-CD40, gemcitabine, nab-paclitaxel, and pembrolizumab in patients with metastatic pancreatic ductal adenocarcinoma (PDAC).
Authors: Bajor David Lawrence , Gutierrez Martin , Vaccaro Gina M. , Masood Ashiq , Brown-Glaberman Ursa , Grilley-Olson Juneko E. , Kindler Hedy L. , Zalupski Mark , Heath Elisabeth I. , Piha-Paul Sarina Anne , Zhou Peigen , Lu Hailing , Ansari Sahar , Hayman Jonathan , Schmitt Michael W. , Coveler Andrew L. 
Published: January 2022

559 Background: SEA-CD40 is an investigational nonfucosylated IgG1 monoclonal agonistic antibody targeted to CD40, expressed on antigen-presenting cells. SEA-CD40 binds with increased affinity to FcγRIIIa resulting in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. PDAC can be treated with gemcitabine + nab-paclitaxel (GnP), often with poor survival. Combining chemotherapeutic agents with SEA-CD40 could facilitate robust antigen release and amplified presentation to CD8+ T cells. In preclinical models, the combination of SEA-CD40 and chemotherapy resulted in significant antitumor activity which is further enhanced with anti-PD1 treatment. We present data from an ongoing Phase 1 study (SGNS40-001) in a PDAC cohort evaluating the combination of SEA-CD40, GnP, and pembrolizumab (pembro). Methods: Patients (pts) ≥18 years old with untreated metastatic PDAC and Eastern Cooperative Oncology Group performance scores of 0 or 1 were enrolled. GnP were administered on Days 1, 8, and 15 of each 28-day cycle with 10 or 30 μg/kg SEA-CD40 IV on Day 3. Pembro was administered every 42 days starting on Day 8. Results: As of July 9, 2021, 61 pts were treated: 40 and 21 pts at 10 and 30 μg/kg SEA-CD40, respectively. Minimum follow-up was 5 months. The most frequent treatment-emergent adverse events (TEAEs) are shown in Table. 5 (8%) pts experienced an AE leading to treatment (tx) discontinuation (3 and 2 in 10 and 30 μg/kg SEA-CD40 dose, respectively), 35 (57%) pts experienced a serious TEAE (22 and 13 pts in 10 and 30 μg/kg, respectively). Two tx-related deaths occurred: colitis attributed to pembro, and septic shock attributed to GnP. Pts had transient increases in circulating cytokines and chemokines associated with immune activation and trafficking as well as increases in markers of activation on peripheral NK cells and T cells. Conclusions: The combination of SEA-CD40 + GnP + pembro demonstrated a tolerable safety profile. Evidence of immune activation was observed, consistent with the proposed mechanism of action. Follow-up for response and survival are ongoing. Clinical trial information: NCT02376699. [Table: see text]
A phase II study of niraparib and dostarlimab with radiation in patients with metastatic pancreatic cancer.
Authors: Parikh Aparna Raj , Weekes Colin D. , Blaszkowsky Lawrence Scott , Franses Joseph Wang , Ting David Tsai , Mehta Arnav , Roeland Eric , Ryan David P. , Allen Jill N. , Clark Jeffrey William , Ly Leilana , Loosbrock Isabella , Jarnagin Joy X. , Bannon Allison , Caldwell Darcy K. , Yeap Beow Y. , Wo Jennifer Y. , Hong Theodore S. 
Published: January 2022

564 Background: PARP inhibitors have activity as monotherapy in BRCA1/2 mutated metastatic pancreatic cancer; however, several other genes and associated proteins exist in the homologous recombination repair (HRR) pathway promoting resistance to chemotherapy and radiation-induced damage. Tumors with HRR deficiency have an impaired ability to repair themselves and are susceptible to PARP inhibition, but ionizing radiation can also induce DNA breaks. Ongoing research suggests that PARP inhibitors may cause radio-sensitization and may also enhance sensitivity to immunotherapy. We conducted a phase 2 study of niraparib and dostarlimab with radiation in a biomarker unselected PDAC population given PARP inhibitors' immunomodulatory and radiosensitizing effects. Methods: In this open-label, single-arm, phase-2 study, eligible patients had histologically confirmed MSS PDAC, ECOG PS 0-1, and progressed on at least one line of jm. Treatment consisted of niraparib 200 mg daily on a 21-day cycle, dostarlimab 500 mg every 3 weeks every 4 weeks for the first four doses, then 1000 mg every 6 weeks, and 3 fractions of 8 Gy at Cycle 2. Treatment continued until progressive disease, discontinuation, or withdrawal. The primary endpoint was DCR by RECIST 1.1 with radiological evaluations every 3 months. Secondary endpoints included DCR by irRECIST, PFS, OS, and safety. Responses were defined as disease control outside the radiation field. We obtained serial tumor biopsies, including pre-treatment. A two-stage design was used, requiring disease control in at least one of the first 15 patients before proceeding to the full accrual of 25 patients. Intention to treat analysis included all patients receiving at least one dose of any study agent. Results: We enrolled and treated 15 pts (median age 60 years [range 37-77], 53% male) from 08/2020 to 05/2021. Overall, DCR was 0/15 (95% CI: 0-22%), median PFS was 1.6 months (95% CI: 1.1-2.7), and median OS 3.1 months (95% CI: 1.5-7.7). Among 27 treatment-related serious adverse events, 15 (56%) were grade 3, including decreased CD4 lymphocytes, thrombocytopenia, anemia, and fatigue being the most common. Conclusions: The combination of niraparib and dostarlimab with radiation did not meet the pre-specified criteria for expansion to full accrual. Further analyses of dose intensity in this heavily pretreated and evaluation of in-field responses are underway. Further investigation of the combination with biomarker selection is warranted. Clinical trial information: NCT04409002.
Real-world clinical outcomes of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) treated with liposomal irinotecan-based regimens: Impact of prior irinotecan (IRI) exposure.
Authors: Yu Kenneth H. , Cockrum Paul , Surinach Andy , Lamarre Neil , Wang Shu , O'Reilly Eileen Mary 
Published: January 2022

580 Background: Subgroup analyses of the NAPOLI-1 study identified that among patients who were IRI naïve prior to entering the clinical trial, a survival benefit was observed between the study arm and control arm (overall survival (OS): 6.7 months vs 4.2 months). This treatment benefit was not observed among those previously exposed to IRI (OS: 4.6 months in study arm vs 4.8 months in control arm). This study sought to understand the impact of prior exposure to IRI on clinical outcomes among patients treated with liposomal irinotecan in the real-world setting. Methods: This retrospective observational study utilized the Flatiron Health EHR database. Data were analyzed for adult patients with mPDAC treated with liposomal irinotecan -based regimens between January 2016 and October 2020. Patient characteristics, OS and progression-free survival (PFS) were assessed. Prior IRI was defined as IRI given in a prior regimen in the metastatic setting. Cox proportional hazard (PH) methods were used to calculate hazard ratios (HRs). HRs were adjusted to account for demographics and relevant clinical covariates. Patients without prior exposure to IRI were used as the reference population for the Cox PH model (an HR < 1 represents worse survival for unexposed patients relative to the exposed). Results: 675 patients with mPDAC treated with a liposomal irinotecan-based regimen were included. Median age at treatment initiation was 69 (IQR: 62 – 75) years and among patients with available ECOG performance status (PS), 77.4% had a PS of 0-1. 181 (27%) patients were previously exposed to IRI in the metastatic setting (Table). The unadjusted OS HR was 1.3 (95% CI: 1.1 – 1.6, p < 0.001) and the unadjusted PFS HR was 1.4 (95%CI: 1.2 – 1.7, p < 0.001). After adjustment for baseline characteristics the adjusted OS HR was 1.0 (95% CI: 0.8 – 1.3, p = 0.8836) and the adjusted PFS HR was 1.1 (95%: 0.8 – 1.4, p = 0.5626). Conclusions: The results of this study suggest prior exposure to IRI is not a predictor of worse clinical outcomes for patients treated with liposomal irinotecan-based treatment when accounting for key clinical characteristics in a multivariable model. The results from this real-world study can be used to support treatment sequencing decisions for patients with mPDAC following first line therapy. This is the largest real-world evidence study to date of patients with mPDAC treated with liposomal irinotecan.[Table: see text]
Promising survival and disease control in third-line or greater metastatic or locally advanced pancreatic cancer patients following chemo-radiation and novel combination of aldoxorubicin, N-803 IL-15 superagonist, and PDL1- NK cell therapy.
Authors: Seery Tara Elisabeth , Nangia Chaitali Singh , McKean Heidi Ann , Sender Leonard S. , Bhar Paul , Reddy Sandeep K. , Soon-Shiong Patrick 
Published: January 2022

582 Background: Pancreatic cancer claimed an estimated 47,050 lives in the USA in 2020, with an expected median overall survival (OS) of 3 months in 3rd line. (Manax ASCO GI 2019), with no evidence of disease control in these late stage patients. We hypothesize that effective response against pancreatic cancer requires orchestration of both the innate and adaptive immune system to accomplish immunogenic cell death with survival benefit. Herein we report the first results of a novel combination immunotherapy protocol of low-dose chemoradiation, cytokine-induced NK and T cell activation via N-803 (an IL-15 cytokine superagonist), and allogeneic off-the-shelf PDL1-targeted high-affinity NK cell (PDL1 t-haNK) infusion. Methods: We report data from a multi-center study, on 55 3rd line or greater, subjects treated with low dose, chemo radiation Nab-paclitaxel (100 mg/ m2 IV), Gemcitabine (600 mg/m2 IV); Cyclophosphamide (50 mg PO BID) and low dose SBRT. This induction immuno-modulation therapy to induce DAMPs was followed with investigational agents activating the innate and adaptive systems: Aldoxorubicin (150 mg/m2 IV), N-803, an IL-15 superagonist (15 μg/kg SC) and PD-L1 t-haNK (̃2 × 109cells/dose IV). Prophylactic G-CSF or EPO was not allowed. All treatments were administered on an outpatient basis. Results: As of submission, median follow-up is 3.9 months. Median age 62, M:F ratio 35:20. ECOG 0-1,92%. 41/55 (75%) subjects reported a grade ≥3 AE related to the chemo radiation, anemia 44%, neutropenia 24%, thrombocytopenia 11%, all others < 10%. SAEs attributed to investigational agents were reported in 5/55 (9%) patients. Of the 44 patients evaluable at 3 months to date, the OS is 81.8% (36/44), 95% CI: 67.3%, 91.8%. The disease control rate of 47 evaluable patients is 36.2% (17/47) 95% CI 22.7%,51.5%. No treatment related deaths have occurred. Treatment is ongoing for 16 subjects, with 14 months as the longest duration on therapy to date. Median OS not yet reached with 28/55 alive to date. Median PFS is 2.4 months (95% CI: 2.0, 3.7) and 36% of subjects not having progressed to date. Conclusions: Historical 3 month median OS in 3rd line metastatic pancreatic cancer patients has been exceeded. Early safety and promising efficacy is seen in QUILT 88 investigating a novel combination immunotherapy protocol of low-dose chemoradiation, N-803 and PDL1 t-haNK therapy. Updated data will be presented. Clinical trial information: NCT04390399.
Palliative radiosurgery for localized pancreatic cancer in the elderly.
Authors: Sckolnik Steven , Fishel Rotem , Borazanci Erkut Hasan , Amini Albert , Thosani Amar 
Published: January 2022

583 Background: At least 15% of patients diagnosed with localized pancreatic cancer are medically unfit for surgical resection or systemic therapy. Traditionally, these patients are enrolled in palliative care with symptom management alone. With local progression of their disease, they may experience pain, obstruction, weight loss and nausea. Radiosurgery is a localized high dose conformal therapy allowing for noninvasive treatment of pancreatic cancer. This study retrospectively examines the role of palliative radiosurgery as monotherapy for elderly patients who are not candidates for standard of care therapy. Methods: From 2017-2021, 28 patients over the age of 80 with biopsy confirmed pancreatic adenocarcinoma and localized disease by imaging were retrospectively evaluated. All had been deemed not to be candidates for surgical resection or systemic chemotherapy. Outcomes were reviewed to evaluate patient characteristics, local control, quality of life, ECOG status and survival duration. Results: Median patient age was 84 years (range 80-99). All 28 patients received SBRT radiosurgery to the pancreas with 35-40Gy in 5 fractions with photon LINAC platform. Mean ECOG score was 1.2 at time of treatment. At 6 month follow up, 18 patients were alive with a mean ECOG of 1.4. Four patients reported grade 2 acute GI toxicity in the first three months with no late toxicity reported. Eight patients developed local progression while fourteen patients developed distant metastatic disease. Six patients at least one year out from treatment have no evidence of disease progression. Median overall survival is 10.8 months. Conclusions: Pancreatic radiosurgery is a safe and effective method of palliative therapy for elderly patients who are not candidates for surgical resection or systemic therapy. It can provide durable local control, relief of pain and obstructive symptoms, is well tolerated with minimal toxicity and provides favorable survival when compared to palliative care alone.