bluuebunny/crossref_metadata_2025 huggingface dataset:
Initially unresectable hepatocellular carcinoma treated by combination therapy of tyrosine kinase inhibitor and anti-PD-1 antibody followed by resection.
Authors: Sun Hui-Chuan , Zhu Xiao-Dong , Huang Cheng , Shen Ying-Hao , Ji Yuan , Ge Ning-Ling , Tan Chang-Jun , Zhou Jian , Fan Jia
Published: May 2020

e16690

Background: Combination of tyrosine kinase inhibitor (TKI) and anti-PD-1 antibody showed a high tumor response for advanced hepatocellular carcinoma (HCC). We are aiming to study the effect of combination therapy followed by resection in pts with initially unresectable HCC. Methods: 60 consecutive pts with unresectable or advanced HCC were treated with combination therapy as first-line treatment, including 2 in BCLC-A (China Liver Cancer stage [CNLC]-Ib), and 13 in BCLC-B (CNLC-IIa and IIb), 26 in BCLC-C (vascular invasion, CNLC-IIIa) and 19 in BCLC-C (extrahepatic metastasis, CNLC-IIIb). Tumor response and resectability were evaluated by imaging every 2 months (± 1 week). The criteria of resectability included: (1) R0 resection can be achieved; (2) remnant liver volume ≥ 40%; (3) Child-Pugh score is 5; (4) no contra-indications for hepatectomy. Results: Conversion to resectable HCC was identified in 11 (18.3%) pts after combination therapy. Of them, 2 pts are still under treatment for immune-related adverse events, and 9 underwent hepatectomy as of January 2020. Of the 9 pts, the initial tumor was unresectable because of macro-vascular invasion (n = 6, 1 Vp3, 3 Vp4, 1 hepatic vein, 1 inferior vena cava), extrahepatic metastasis (n = 1, right adrenal gland), tumor nodules ≥ 4 (n = 1) and recurrent HCC within 2 months after first resection (n = 1). The TKIs used were lenvatinib (n = 6) and apatinib (n = 3); anti-PD-1 antibodies used were pembrolizumab (n = 4), sintilimab (n = 3), camrelizumab (n = 1) and nivolumab (n = 1). The median interval between start of combination therapy and resection was 99 days (range, 73–251). The median post-operative hospital stay was 14 days (range, 11–68). The prevalence of post-hepatectomy liver dysfunction (the criteria by ISGLS) is 5 (55.6%) pts, and the post-operative complications (by Clavien–Dindo classification) occurred in 4 (44.4%) pts, including grade I in 1, grade IIIa in 2, and grade V in 1 (died from immune-related adverse events). Tumor response (RECIST v1.1) evaluated before surgery were PR (n = 5), SD (n = 3), and PD (n = 1). Pathological CR (pCR) was found in 5 (55.6%) cases. After a median follow up of 72 days (range, 11–184), tumor recurrence were diagnosed in 1 patient, and mortality without tumor recurrence in 1 patient, the other 7 cases remained tumor-free. Conclusions: This is to date the largest cohort of pts underwent R0 resection after combination therapy for initially un-resectable HCC. The combination of a TKI and anti-PD-1 antibody is feasible as a conversion therapy.
Characteristics of growth factors in the blood allowing determination of neuroendocrine component in pancreatic diseases.
Authors: Frantsiyants Elena M. , Kaplieva Irina V. , Surikova Ekaterina I. , Neskubina Irina V. , Bandovkina Valeria A. , Trepitaki Lidia K. , Pogorelova Yulia A. , Nemashkalova Ludmila A. , Aleynov Viacheslav A. , Trifanov Vladimir S. , Grechkin Fedor N. , Sanamyants Sergey V. , Kit Oleg I. , Nepomnyashchaya Evgeniya M. , Petrov Dmitry S. , Fomenko Yuriy A.
Published: May 2020

e16693

Background: Insulin-like growth factors I and II (IGF-I and II), transforming growth factor β (TGFβ) and its receptor (TGFβR2) are involved in cancer pathogenesis. At the same time, the features of these parameters in the blood related to the disease nature have yet to be determined. The purpose of the study was to analyze the dynamics of IGF-I, IGF-II, TGFβ and TGFβR2 in the blood of patients with pancreatic cancer. Methods: The study included male patients with pancreatic adenocarcinoma T1-3N0-1M0 (A, n = 18), pancreatic neuroendocrine tumors (NET, n = 12) and pancreatic adenocarcinoma with the neuroendocrine component T1-3N0-1M0 (A+NEC, n = 12) before the treatment. Healthy males (n = 21) were controls. Blood levels of IGF-I and IGF-II were measured by ELISA using standard test systems (Meddiagnost, Germany), as well as levels of TGFβ (BenderMedSystem, Austria) and TGFβR2 (RayBiotech, USA). Results: Patients with pancreatic cancer showed increased blood levels of IGF-II: in PA – by 1.9 times (p˂0.05), in NET – by 2.7 times and in A+NEC – by 3.4 times compared to values in healthy donors. TGFβ was elevated only in patients with A by 1.5 times (p˂0.05). TGFβR2 in the blood of patients with NET and A+NEC was increased by 4.8 and 4.5 times respectively, while in patients with A it was similar to control values. The TGFβ/TGFβR2 ratio was calculated; A+NEC was prognosed in patients with its level of 1.32±0.2. Conclusions: High blood levels of IGF-II were registered in patients with pancreatic cancer. The TGFβ/TGFβR2 ratio served as informative laboratory tests to predict the nature of pancreatic disease.
Cohort 1 results of a phase I study of autolytic immunotherapy of metastatic neuroendocrine neoplasms using intralesional rose bengal disodium.
Authors: McGregor Mark , Price Timothy Jay , Cehic Gabby , Kirkwood Ian D. , Sebben Ruben , Reid Jessica J. , Neuhaus Susan , Wachter Eric Andrew , Maddern Guy
Published: May 2020

e16694

Background: Metastatic neuroendocrine neoplasms (mNEN’s) originating in the gastrointestinal tract are frequently slow growing yet both symptom and disease control remain important. Treatment options include resection, chemoablation, systemic somatostatin analogues (SSA) or peptide receptor radionuclide therapy (PRRT), but additional options are needed, especially when available options have been exhausted. Intralesional (IL) rose bengal disodium (PV-10), an autolytic immunotherapy under development for solid tumors, is being investigated as a potential option for treatment-refractory patients (pts) with hepatic metastases. Methods: This phase 1 study is evaluating the safety, tolerability and objective response resulting from percutaneous administration of PV-10 in 12 pts with progressive mNEN refractory to SSA and PPRT; pts must have at least one injectable hepatic lesion (1.0-3.9 cm in longest diameter) not amenable to resection or other potentially curative therapy. In Cohort 1 (n = 6) pts received PV-10 to a single hepatic lesion per treatment cycle, and could receive PV-10 to additional uninjected hepatic lesions ≥6 weeks after prior injection. The primary endpoint is safety. Secondary endpoints include objective response rate assessed by independent review of contrast enhanced CT and by 68Ga-DOTATATE PET. Results: Cohort 1 has fully enrolled, with 4 of 6 pts male, median age 65 yrs, range 47-72. Primary sites were: small bowel 3, pancreas 2, caecal 1. NET grade: Gd1 = 5, Gd2 = 1. All pts had progressed on prior SSA and PRRT. Median baseline CgA was 645 (range 30-2819). One pt received 4 PV-10 treatment cycles, 1 received 2 cycles, and 4 received a single cycle. Toxicity was acceptable, including transient pain post procedure, carcinoid flare and nausea. A partial response of injected lesions was observed in 50% of pts (injected lesion progression in 1 pt), with an overall response of stable disease achieved in 84% of pts by RECIST 1.1 (progressive disease in 1 pt). Progression free survival (PFS) was not reached by CT (range 2.4-25.3+ months), and was 6.1 months by PET. Median overall survival (OS) was ≥22.5 months, with three subjects alive at the data cut-off of Jan 2020 (range 18.1-33.8 months). Conclusions: Hepatic IL PV-10 elicited no safety concerns with encouraging evidence of both local response of injected tumors and prolonged systemic disease control in some pts. Enrolment to Cohort 2 is nearing completion where an additional 6 pts may receive injection of multiple lesions per treatment cycle. Clinical trial information: NCT00986661 .
Prooxidant effect of α-tocopherol in pancreatic tumors.
Authors: Surikova Ekaterina I. , Frantsiyants Elena M. , Goroshinskaya Irina A. , Trifanov Vladimir S. , Aleynov Viacheslav A. , Nemashkalova Ludmila A. , Neskubina Irina V. , Chernyak Maksim N. , Sanamyants Sergey V. , Gabrichidze Petr N. , Kit Oleg I. , Zhukova Galina V. , Fomenko Yuriy A. , Petrov Dmitry S.
Published: May 2020

e16698

Background: The coexistence of neuroendocrine tumors and pancreatic adenocarcinoma is rare, and treatment of such mixed tumors is challenging due to the differences in their natural course and response to systemic therapy. There is growing evidence that vitamins affect the biology of pancreatic tumors. The purpose of the study was to measure concentrations of retinol (RET), α-tocopherol (α-TCP) and diene conjugates (DC) in the blood of patients with pancreatic cancer in order to reveal its pathogenetic characteristics. Methods: Blood levels of RET and α-TCP (ELISA methods, Cloud-Clone Corp, USA), their ratio and DC concentrations (biochemical method) were measured before treatment if 42 patients with pancreatic cancer: adenocarcinoma (AC), T1-3N0-1M0, n = 9; AC with a neuroendocrine component (AC+NE) (up to 30%), n = 21; neuroendocrine tumors (NET), T1-3N0-1M0, n = 12. 22 healthy men of similar age were controls. All patients gave their voluntary informed consent for the study. Results: RET levels in all patient were statistically significantly lower than in controls: in AC by 3.8 times, in AC+NE by 1.9 times, in NET by 3.7 times (p = 0.0000). Concentrations of α-TCP in AC were 1.6 times (p = 0.0011) lower than in controls, in AC+NE were similar, and in NET α-TCP was 1.5 times higher than in controls (p = 0.0000). The ratio of α-TCP/RET in all patients significantly exceeded control values: in AC by 2.2 times, in AC+NE by 1.6 times, in NET by 5.7 times (p = 0.0000). Levels of DC in all patients were higher than in controls: in AC by 2.5, in AC+NE by 2.1, in NET by 2.7 times (p = 0.0001). Conclusions: Changes in serum levels of RET and α-TCP differ in patients with AC, NET and mixed tumors, which causes changes in the balance of vitamins and can contribute to a prooxidant effect, as evidenced by an increase in DC levels.
Phase II study of ONC201 in pheochromocytoma-paragangliomas (PC-PG), medullary thyroid carcinoma (MTC), and other neuroendocrine tumors.
Authors: Anderson Peter Meade , Zahler Stacey
Published: May 2020

e16703

Background: ONC201 is an imipridone with specificity for the dopamine-like DRD2 receptor. Anti-cancer effects involve up-regulation of TRAIL/DR5, dual AKT/ERK pathway inhibition, and integrated stress response. Because TCGA analysis showed very high DRD2 expression in neuroendocrine tumors, especially pheochromocytoma-paragangliomas (PC-PG), an investigator initiated IND study of ONC201 in neuroendocrine tumors (CCF IRB17-808; CASE2716; IND132665; NCT03034200) was done. Methods: ONC201 dose was 625 mg po/wk. Metastatic PG-PG were enrolled in cohort A. Other neuroendocrine patients were entered in cohort B. Two additional patients had single patient IND. Because hypertension is an issue from catecholamine producing PC-PG, all PC-PG patients had combined alpha + beta blockade and bp was monitored in the clinical research unit after dose #1 ONC201. Additional data was obtained with daily home bp monitoring, often with a wireless cuff which connects into EPIC via MyChart. Labs, scans, and clinic visits were done at week 6, then every 3 months from initial ONC201 dose. Patients with clinical benefit remained on study and could get radiation for bone metastases. Results: Neuroendocrine tumors were treated with ONC201 included 10 PC-PG, 3 with MTC 13 with other varieties including sarcomas, adrenal cortical carcinoma (ACC), neuroblastoma, and GI neuroendocrine tumor (NET). ONC201 was exceptionally well tolerated. All patients were able to maintain or improve KPS while on study. No adverse effects on bp were seen. The only ONC201-related AE was temporary grade 1 neurocognitive dysfunction for ~36 hours after weekly ONC201 dosing in 2/10 PC-PG patients. 4/10 PC-PG patients remain on study at 28, 22, 22, and 4 month. 1 DSRCT patient achieved a PR at 3 months and has been treated 28 months. An ACC patient was initially responsive (PR), but rapidly progressed in liver; 1 GI NET patient had -10% reduction by RECIST at 3 months and remains on treatment. MTC may be responsive (1 no response, 2 stable and improving by RECIST at 3 months). Conclusions: ONC201 is very well tolerated with excellent quality of life and extended clinical benefit against neuroendocrine tumors. Although ONC201 has activity against neuroendocrine tumors, especially PC-PG, increased efficacy will likely require combination therapy. Clinical trial information: NCT03034200 . [Table: see text]
Molecular correlation of the activity of evofosfamide (EVO) in combination with sunitinib (SUN) in pancreatic Neuroendocrine Tumors (pNETs) in the SUNEVO GETNE Trial.
Authors: López-López Carlos , Alonso Gordoa Teresa , Benavent Marta , Capdevila Jaume , Teule Alex , Custodio Ana , Sevilla Isabel , Santos Maria , Lanillos J. , Rodríguez-Antona Cristina , Garcia-Carbonero Rocio , Grande Enrique
Published: May 2020

e16706

Background: MEN1, DAXX, ATRX, and PI3K/AKT/mTOR pathway genes are frequently mutated in pNETs. Sunitinib is approved and widely used in the metastatic setting but unfortunately, no validated predictive biomarker has been identified to guide therapy yet. The SUNEVO phase II trial of the Spanish Task Force Group for Neuroendocrine and Endocrine Tumours (GETNE) trial combined the pro-drug of EVO under SUN-induced hypoxic conditions. Methods: We performed an exploratory analysis aimed to identify somatic mutations associated with the clinical benefit of pNET patients treated with SUN+EVO combination. Seventeen treatment-naïve pts with pNETS were included in the SUNEVO trial, and 4 (23.5%) achieved a partial response (by RECIST 1.1). Tumor DNA from 10 FFPE tumor samples were successfully sequenced with an enrichment panel (Nimblegen, Roche) including 42 cancer-related genes and TERT promoter region. Median coverage was 793x. Coding non-synonymous and loss-of-function variants were considered for the analysis. Final analysis included tumor samples from the 10 patients with NGS results. Results: Somatic mutations were found in MEN1 (70%), DAXX (30%), ATRX (20%), SETD2 (20%) and PTEN (10%). Mutations in the telomere maintenance genes DAXX and ATRX were concordant with mutual exclusivity. The loss of MEN1 was associated with a greater number of mutations (p = 0.019). Patients with complete and partial response showed heterogeneous genetic profiles. Conclusions: The molecular alterations of the patients in the SUNEVO trial were consistent with those previously described for metastatic pNETs. No clear association between molecular defects and treatment response was found. Clinical trial information: NCT02402062 .
Survey of challenges in access to diagnostics and treatment for neuroendocrine tumor (NET) patients (SCAN): Awareness of specialized techniques and latest interventions.
Authors: McDonnell Mark , Van Genechten Dirk , Kolarova Teodora , O'Toole Dermot , Singh Harjit , Chen Jie , Howe James R. , Singh Simron , Bouvier Catherine , Rodien-Louw Christine , Leyden Simone , Dureja Sugandha
Published: May 2020

e16708

Background: SCAN measured global readiness to provide diagnostics and treatments for NET patients in terms of awareness, availability, quality and affordability. This analysis focused on patient and healthcare professional (HCP) awareness of NET diagnostics and treatments. Methods: During Sept-Nov 2019, NET patients and HCPs completed an online survey (available in 14 languages). Results: There were 2795 respondents from 68 countries across 6 continents (2359 patients/carers; 436 HCPs). Primary NETs were most often gastroenteropancreatic NETs (GEP NET; 71% [1408/1983]), particularly small intestinal (35% [690/1983]) or pancreatic (20% [402/1983]). Biopsy was the most well-known diagnostic option in the overall NET patient group (82% [1917/2325]), the GEP NET patient subgroup (83% [1156/1395]) and HCPs (94% [411/435]), followed by CT (all patients: 81% [1874/2325]; GEP NET: 80% [1118/1395]; HCPs: 86% [376/435]). More HCPs were aware of specialized diagnostics, such as 68Ga-DOTA PET CT (HCP 81% [353/435]) and chromogranin A (CgA; 79% [344/435]), than patients (all: 68% [1574/2325] & 62% [1451/2325], respectively; GEP NET: 69% [962/1395] & 67% [936/1395]). The vast majority of all patients (87% [1983/2275]), GEP NET patients (89% [1215/1363]) and HCPs (91% [392/431]) knew surgery was a treatment option. Somastatin analogues were recognised as a treatment option by 90% of HCPs (387/431), but only 75% of GEP NET patients (1019/1363) and 70% of all NET patients (1599/2275). Nearly a quarter of HCPs (22% [95/431]) and one-third of patients (all: 33% [755/2275]; GEP NET: 30% [409/1363]) had not heard of peptide receptor radionuclide therapy (PRRT). The majority of patients (all: 88% [2007/2273]; GEP NET: 89% [1213/1370]) and HCPs (93% [396/425]) were aware of conventional imaging, such as CT/MRI/ultrasound, being used for ongoing monitoring of NETs. Approximately a third of all NET patients and a quarter of HCPs were unware CgA (patients: 32% [723/2273]; HCPs: 22% [94/425]) or 68Ga-DOTA PET CT (patients: 29% [670/2273]; HCPs: 24% [102/425]) were ongoing monitoring tools. Similarly, CgA and 68Ga-DOTA PET CT were not recognized by 27% of GEP NET patients (364/1370 & 371/1370, respectively). Conclusions: Increased awareness of NET diagnostics and treatments, particularly newer, more specialized tools, amongst both HCPs and patients is required to ensure continued advancements and improvements in the global standard of care for NETs.
Distinct clinical characteristics in young-onset pancreatic neuroendocrine tumor: A propensity-adjusted analysis.
Authors: Goksu Suleyman Yasin , Ozer Muhammet , Kazmi Syed Mohammad Ali , Sanford Nina Niu , Aguilera Todd Anthony , Hsieh David , Sanjeevaiah Aravind , Verma Udit , Khosama Leticia , Maxwell Mary Claire , Bleeker Jonathan , Atiq Muslim , Beg Muhammad Shaalan
Published: May 2020

e16710

Background: Pancreatic neuroendocrine tumor (PNET) is a rare disease. There is a lack of data on the association of age and sociodemographic characteristics on survival in patients with NET. Our study aimed to evaluate clinical, molecular differences, and survival outcomes in young-onset PNET (YOPNET) and late-onset PNET (LOPNET). Methods: We used the National Cancer Database to identify patients with YOPNET ( < 50 years) and LOPNET (≥50 years) who underwent definitive surgery diagnosed between 2004 and 2015. We calculated the survival outcomes using Kaplan Meier and Cox regression methods before and after 1:1 nearest neighbor propensity score matching. We used the AACR Genie cohort to compare mutation frequency with the Benjamini-Hochberg method between YOPNET and LOPNET. Results: A total of 6,259 patients with PNET were selected, of which 27% were YOPNET. Patients with YOPNET were more likely to be female, black, and Hispanic, have private insurance versus LOPNET (all p < .001). Patients with YOPNET had less comorbidity score, but greater tumor size ( > 4 cm) and higher stage (all p < .001). Patients with LOPNET were more likely to be treated in an academic/research facility ( p < .001). Patients with YOPNET were more likely to be located in the head of the pancreas ( p = .004). Patients with YOPNET had better overall survival (OS) as compared to patients with LOPNET which persisted after propensity score matching ( p < .001). This difference continued after adjusting for clinically significant variables (unmatched p = .008; matched p = .01) (Table). For genomic analysis, we identified 177 patients; 27% was YOPNET, and patients with YOPNET had a significantly lower rate of MEN1 mutation than patients with LOPNET (26% vs. 56%, p < .001). Rate of other mutations was not different. Conclusions: Patients with YOPNET who underwent surgery had better OS than LOPNET and were more likely to have higher stage and greater tumor size. YOPNET represents a disease with distinct clinical and molecular features. [Table: see text]
Patient-derived organoids as a potential tool for clinical decision in advanced gallbladder cancer.
Authors: Obreque Javiera , Vergara Luis , Suarez Felipe , Garcia Patricia , Marcelain Katherine , Toro Jessica , Rivas Solange , Rosa Lorena , Roa Juan Carlos , Nervi Bruno , Viñuela Eduardo , Aguayo Gloria , Muñiz-Muñoz Sabrina , Caire Nicole , Escalante Anrried , Mondaca Sebastian , Bizama Carolina
Published: May 2020

e16717

Background: Human gallbladder cancer research lacks in vitro models that can recapitulate the pathophysiology of the original tumor and normal epithelia. Organoids cultures emulate the tumor heterogeneity and have been successively used as translational models to evaluate clinical response to anticancer drug. Here, we established and characterized patients derived organoids culture (PDOs) from human gallbladder cancer patients. Methods: Fresh tissues obtained from gallbladder cancer patients who underwent cholecystectomy were digested with Collagenase/Dispase, filtered and then suspension cells were mixed with Matrigel (1:1) for organoids establishment. Cultures were maintained at 37°C and 5% CO2. The organoids were characterized through histopathology evaluation, immunohistochemistry, and ultra-deed targeted sequencing (TruSeq protocol, Illumina, TSACP; 25 genes). In addition, we evaluated the response of organoids to gemcitabine, cisplatin and Fluorouracil (5-FU), using the CellTiter-Glo 3D luminescence assay. Results: We have successfully established PDOs cultures from six patients with gallbladder adenocarcinoma with a 60% efficiency (6/10). The PDOs recapitulated the histological features and maintained the expression of CK19, Ki67, P53 as compared with the epithelia of primary tumors. Moreover, the PDOs maintained the mutational status of major driver genes, including TP53 and PIK3CA. Finally, tumor organoids showed differential response to standard chemotherapy treatment. GBC-PDO2 and GBC-PDO4 showed high resistant to gemcitabine (IC50 > 10μM), which suggests that the personalized treatment is necessary for generate better response. Conclusions: the established gallbladder tumor organoids exhibited similar histological and genomic features in relation to their original epithelia. PDOs can be considered a valuable tool for future research aimed to understand gallbladder cancer biology and for developing personalized-medicine approaches for advanced gallbladder cancer patients. (Funding Source: FONDECYT #1171463, FONDECYT #1170893 and Fondef IT16I10051).
Intraoperative electrochemotherapy in locally advanced pancreatic cancer: Results and impact on quality of life. a single center experience.
Authors: Di Marco Mariacristina , Ricci Claudio , Carloni Riccardo , Grassi Elisa , De Lorenzo Stefania , Palloni Andrea , Abbati Francesca , Andrini Elisa , Di Federico Alessandro , Ricci Angela Dalia , Ingaldi Carlo , Serra Carla , Alberici Laura , De Raffele Emilio , Guido Alessandra , Minni Francesco , Rizzo Alessandro , Brandi Giovanni , Pantaleo Maria A. , Casadei Riccardo
Published: May 2020

e16731

Background: Locally advanced pancreatic cancer (LAPC) is usually treated with chemoradiotherapy with poor results, thus additional therapies have been proposed. Of the latter, electrochemotherapy (ECT) represents a non-thermal ablation method, which combines the administration of chemotherapeutic drugs with permeabilizing electric pulses for cell membrane electroporation. The present study is the first to assess the short and long-term results, and the quality of life of the patients who underwent ECT for LAPC. Methods: Observational study of patients affected by LAPC who underwent intraoperative ECT after chemoradiotherapy. The inclusion criteria were: 1- patients with LAPC (defined according to the National Comprehensive Cancer Network 2019), 2- previous chemoradiotherapy and 3- absence of disease progression at restaging. Data at diagnosis and at restaging were collected for each patient. The Quality of life was evaluated using the Euro Quality of Life Group Association Questionnaire (EQ-5D-5L). The questionnaire was administered to all patients before and after ECT. Results: From May 25, 2018 to November 26, 2019 five patients underwent ECT: in 4 cases, the tumors were located in the head and, in one, in the body of the pancreas. Preoperative chemotherapy consisted mainly of 6 cycles of modified folfirinox, while the radiotherapy consisted of 54 Gy (27 fractions). At restaging, the serum value of CA 19-9 and tumor size were reduced; however, the vascular involvement did not change. No downstaging was recorded. Intravenous bleomycin 15,000IU/m2 was given as a bolus, the ECT procedure was performed using at least 4 needles with a mean duration time of 27 minutes, (range 15-40). No postoperative mortality or major complications were reported. The mean length of stay was 8 days (range 5-14). Four patients were alive and well at the end of the study while one patient died from disease progression. The mean follow-up was 20.8 months (range 9-34) from diagnosis and 9.4 months (range 2-19) from ECT. The quality of life was good (EQ-5D-5L scale > 50 in all cases) and there was improvement in pain/discomfort with respect to the pre-treatment period in 3 out of 5 patients. Conclusions: Electrochemotherapy can be considered a simple, feasible and safe palliative additional treatment in LAPC without progression after chemoradiotherapy, and it seems to allow a good quality of life and pain improvement.
Association of losartan use with outcomes in metastatic pancreatic cancer patients treated with chemotherapy.
Authors: Allen Jessica , Mehta Kathan , Anant Shrikant , Dandawate Prasad , Saeed Anwaar , Kasi Anup
Published: May 2020

e16738

Background: A phase II trial has shown improved efficacy of neoadjuvant therapy when combined with losartan (by remodeling desmoplasia) in locally advanced pancreatic ductal adenocarcinoma (PDA). However, role of losartan is unknown in metastatic PDA. We examined the relationship between the use of the angiotensin II receptor antagonist, losartan, at time of diagnosis with clinical outcomes in metastatic PDA pts that received chemo. Methods: We retrospectively evaluated 114 metastatic PDA pts treated at our center between Jan 2000 and Nov 2019. We compared OS, PFS, objective response rate (ORR), and disease control rate (DCR) between pts using losartan at time of cancer diagnosis and a control group of pts not on losartan. A subanalysis was performed based on losartan dose: 100mg dose versus control pts. and based on chemo: FOLFIRINOX or gemcitabine+abraxane. Results: Table shows baseline demographics. No significant difference was found in OS [p = 0.455] or PFS [p = 0.919] in pts on losartan (median 274d, 83d) vs control (median 279d, 111d) [p = 0.466]. No significant difference was found in ORR [p = 0.621] or in DCR [p = 0.497]. No significant difference was found in OS [p = 0.771] or PFS [p = 0.064] in losartan pts (median 347d, 350d) vs control (median 333d, 101d) treated with FOLFIRINOX. No significant difference was found in OS [p = 0.916] or PFS [p = 0.341] in losartan (median 312d, 69d) vs control (median 221d, 136d) [p = 0.916] treated with gemcitabine+abraxane. No significant difference was found in OS [p = 0.727] or PFS [p = 0.790] in 100mg losartan pts (median 261d, 84d) vs control (median 279d, 111d). Conclusions: Pts on losartan at time of diagnosis had no significant difference in OS, PFS, ORR, DCR than control pts. However, a subanalysis of pts treated with FOLFIRINOX revealed a longer PFS with losartan than control but did not meet statistical significance, likely due to small sample size. To confirm if the benefit of losartan + FOLFIRINOX seen in neoadjuvant setting for locally advanced cancer also applies to metastatic cancer, our findings need to be validated in a larger cohort. [Table: see text]
Real-world use of liposomal irinotecan-based regimens among patients (pts) with metastatic pancreatic adenocarcinoma (mPDAC) in the United States (U.S.).
Authors: Kim George P. , Cockrum Paul , Surinach Andy , Koeller Jim M.
Published: May 2020

e16740

Background: The goals of randomized control trials (RCTs) are to make causal inferences and precise treatment comparisons, not to describe large heterogeneous pt populations. RWE allows population-based healthcare decision makers to assess and manage therapeutic and economic options for their pts, including those who would and would not have met inclusion/exclusion criteria of a given RCT and are instead managed under usual care, irrespective of clinical trial protocols. In the pivotal phase 3 trial, NAPOLI-1, 117 pts were treated with liposomal irinotecan + 5-fluorouracil/folinic acid, median age 63 years; 66% were treated first- (1L) or second line (2L), and 91% had performance score ECOG 0 or 1. Pts in the trial had overall survival (OS) of 6.2 months (mos), time to treatment failure (TTF) 2.3 mos, and 27% experienced grades 3-4 neutropenia. The present study describes the patient characteristics and outcomes of pts with mPDAC treated with liposomal irinotecan in the US. Methods: This retrospective observational study used data from Flatiron Health EHR-derived de-identified database from over 280 cancer clinics. Patient characteristics, OS, TTF, and rates of neutropenia during treatment (tx) were assessed in adult pts diagnosed with mPDAC who received liposomal irinotecan based tx between November 1, 2015 and October 31, 2019. Results: 600 pts with mPDAC treated with a liposomal irinotecan based regimen were identified. Of these, 56% were initially diagnosed with stage IV disease, 53% were male, 21% had undergone a previous Whipple procedure, and 61% initiated liposomal irinotecan in the 1L or 2L metastatic setting. Median age at tx initiation was 68 (IQR: 62 – 75) years. 92% of pts were treated in the community setting. Among pts with available ECOG (n = 440), 77.5% were score 0-1. Grade 3/4 neutropenia was observed in 11% (n = 66). Overall, median OS was 5.0 mos [95%CI: 4.2–5.6]. mOS among pts treated in 1L (n = 88), 2L (n = 280), and third line plus (3L+, n = 232) were 6.9 mos [5.3–9.2], 5.4 mos [4.6–6.4], and 4.0 mos [3.4–4.5], respectively. Overall, median TTF was 1.9 mos [1.6–2.1]. TTF by line was 3.5 mos [2.3–4.8] in 1L, 2.1 mos [1.7–2.8] in 2L, and 1.4 mos [1.2–1.6] in 3L. Conclusions: This real-world cohort of pts with mPDAC were older, had worse performance status, and had more prior lines compared to the pivotal trial for liposomal irinotecan. Median OS, TTF, and neutropenia were similar to those previously reported. As expected, pts receiving liposomal irinotecan in earlier lines had higher median OS and TTF.
Evaluation of tumor growth inhibition activity of a novel multi-TRK inhibitor ABP-1119 on pancreatic tumor xenograft model.
Authors: Zhan Zheng-Yun James , Pan Wanlong , Yan Hua
Published: May 2020

e16741

Background: Owing to its high mortality and lack of effective treatments, there is therefore an urgent unmet need to develop novel and more effective treatments for pancreatic cancer (PC). ABP-1119 is a novel and potent multi-TRK Inhibitor for several PC-related prime tyrosine kinases (TRKs), such as EGFR, HER2, ALK, and BTK. Pre-clinical studies with ABP-1119, especially study to evaluate its tumor growth inhibition activity on pancreatic tumor xenograft model, are planned. Methods: (1) Mobility-Shift Assay used to Analyze the multi-TRK (such as EGFR, HER2, ALK, and BTK) Inhibition activity of new anti-tumor compounds, (2) CTG Assay used to analyze the inhibition activity of Mia-Paca-2 Cell Line, (3) Anti-tumor inhibition study of ABP-1119 with the pancreatic cancer nude mice, (4) Safety studies of ABP-1119 for Ames, hERG, and maximum tolerated dose (MTD). Results: It was determined that its multi-TRK inhibition activity (IC50) of ABP-1119 was 0.9nM to EGFR, 4.8nM to HER2, 0.9nM to ALK, and 2.1nM to BTK, respectively. Its inhibition activity for Cell Line Mia-Paca-2 was 0.06 µM. In anti-tumor inhibition study with the Mia-Paca-2 tumor nude mice for 14 days, the anti-tumor inhibition rate of ABP-1119 (50 mg/kg, QD) was over 82% (vs Erlotinib as a positive control, 50mg/kg, QD, inhibition rate: 48%), and no any death and other serious side effects were observed during the nude mice tests. Moreover, for other safety issues, its Ames is negative and hERG is > 30 µM, and no test-article related death or adverse events occurred in MTD studies with ABP-1119 (100mg/kg, QD) for 14 days. ABP-1119 also had very good metabolic stability in Human (T1/2 = 2.5hr). Conclusions: Based on our completed preclinical study results, ABP-1119 is a novel and potent multi-TRK Inhibitor, showing excellent enzymatic activity, prominent in-vitro anti-cancer activity, and good tumor growth inhibition activity with tolerable toxicity in pancreatic tumor xenograft in nude mice model. It is warranted to continue further investigation in pancreatic cancer.
Exceptional sustained responses to ipilimumab/nivolumab (ipi/nivo) in patients (pts) with advanced pancreaticobiliary cancers and germline DNA damage repair (DDR) mutations.
Authors: Terrero Gretel , Datta Jashodeep , Pollack Terri , Naveda Alissette , Abushahin Laith I. , Sussman Daniel A. , Pimentel Agustin , Lockhart Albert Craig , Hosein Peter Joel
Published: May 2020

e16757

Background: Immune checkpoint inhibitors (ICIs) have not shown meaningful clinical activity in unselected pts with pancreaticobiliary cancer. DDR-deficient tumors have increased genomic instability, including increased tumor mutation burden (TMB), more tumor-infiltrating immune cells, and enrichment of a T cell-inflamed signature. We hypothesized that pts with DDR deficiency may be sensitive to ICIs. Methods: Utilizing the IRB-approved database at the University of Miami, we identified pts with advanced pancreaticobiliary cancer with germline DDR mutations who were treated with dual ICI. Results: Eleven pts were identified (3 BRCA1, 4 BRCA2, 1 RAD51C, 1 RAD51D, 1 ATM, and 1 PALB2). There were two complete responses (CR), one partial response (PR), three stable disease (SD), two progressive disease (PD), and three pending evaluation. Evaluable responses are sustained for 22 months (m), 19m, and 7m, respectively. All pts had microsatellite stable tumors and none had high TMB. Among pts with responses, TMB was 4, 8, and 8 mut/Mb, respectively. One pt with a CR had gBRCA1 with pancreatic adenocarcinoma (PDAC) s/p distal pancreatectomy/splenectomy, adjuvant gemcitabine (gem)/capecitabine, biopsy-proven recurrence in lung and retroperitoneum 12m later, initiated ipi/nivo, and achieved a CR ongoing for 22m on nivo maintenance. Second pt with a CR had gBRCA1 and unresectable cholangiocarcinoma (CC), with disease progression after gem/cisplatin (cis), therapy switched to ipi/nivo. After 4 doses, an incidental cerebellar lesion was found which was biopsy-proven CC, therefore taken off treatment. Pt has been in CR for 19m without further therapy. The pt with a PR had RAD51C and metastatic PDAC s/p FOLFIRINOX for 6m, followed by olaparib for 12m. At progression, disease rapidly progressed through 5-fluorouracil/nanoliposomal irinotecan, gem/nab-paclitaxel/cis, and FOLFIRINOX. Pt was initiated on ipi/nivo with immediate improvement in pain and tumor markers; PR ongoing for 7m with continued clinical and tumor marker improvement on nivo maintenance. Additional correlative studies (RNA sequencing, Hyperion Imaging, mutation allele fraction analysis) among responders vs. nonresponders will be reported at the meeting. Conclusions: In this series, 6 out of 8 evaluable pts with advanced pancreaticobiliary cancers had disease control with ipi/nivo. This series suggests that tumors with germline DDR mutations may be responsive to ICIs. Further evaluation is warranted.
A prognostic and predictive nomogram for patients with resected pancreatic cancer and the effect of adjuvant chemotherapy in different risk groups: Data from two large cohorts in Taiwan.
Authors: Wu Hsu , Guo Jhe-Cyuan , Yang Shih-Hung , Chen Jen-Shi , Yeh Ta-Sen
Published: May 2020

e16762

Background: Wide survival difference of pancreatic cancer in the same TNM stage had been demonstrated. Predictive nomogram for resected pancreatic cancer had been published before, but the impact of adjuvant chemotherapy was not incorporated, and the data of Asian people were lacking. We also evaluated the effect of adjuvant chemotherapy in different risk groups according to our nomogram. Methods: Pancreatic cancer patients who underwent curative surgery between 2000/1 and 2013/12 were collected from the Cancer Registry of NTUH as the training cohort. Another cohort from CGMH was studied as the validation cohort. Analyses were performed by IBM SPSS version 21.0. Age, gender, primary tumor location, tumor differentiation, LVI, PNI, T, N, AJCC 7th stage, section margin, and adjuvant chemotherapy were used for univariate and multivariate analysis. Nomogram was built and validated by software R 3.6.1. C-index was used to demonstrate the performance and discrimination ability of nomogram. Results: There were 319 and 245 patients in NTUH and CGMH cohorts. The R0 resection rates were 80.6 and 71.8%, and 24.5 and 63.7% of patients received adjuvant chemotherapy. Median OS were 16.9 and 15.7 months in NTUH and CGMH. AJCC 7th Stage, tumor differentiation, section margin, tumor location, LVI and receiving adjuvant chemotherapy were incorporated in the nomogram. C-index in NTUH cohort was 0.66 (95% CI: 0.62-0.70), which was higher then C-index of AJCC 7th Stage, 0.58 (95% CI: 0.54-0.61). The C-index in the CGMH was 0.65 (95% CI: 0.60-0.69). We grouped the two cohorts into low, medium, and high risk groups according to the nomogram score. In NTUH, there were 50, 208, and 48 patients in the low, medium, and high risk groups. In CGHM, there were 37, 156, and 45 patients in those groups. The Kaplan-Meier curves of OS separated nicely according to different risk groups (log rank p < 0.001). If excluding adjuvant chemotherapy in nomogram, C-index in NTUH was 0.63 (95% CI: 0.59-0.67) and 0.62 (95% CI: 0.58-0.66) in CGMH by the new nomogram. The relative survival hazard ratios of receiving adjuvant chemotherapy were 0.532, 0.626, and 0.358 in high, medium and low risk groups of NTUH and were 0.624, 0.798, and 0.788 in CGMH. Conclusions: The new nomogram with more clinical factors than TNM stage has better prognostic prediction. We add the impact of adjuvant chemotherapy into our predictive model. Adjuvant chemotherapy is important in resected pancreatic cancer, even in low risk population.
Superior therapy response predictions for patients with pancreatic cancer (PDAC) using Cellworks Singula: MyCare-009-05.
Authors: Moffat Gordon Taylor , Watson Drew , Kapoor Shweta , Ghosh Roy Kunal Ghosh , Parashar Rajan , Alam Aftab , Alam Aktar , Tyagi Anuj , Singh Divya , Kumari Pallavi , Choudhary Nikita Ray , Gupta Neha , Elangovan Preethi , Mandal Rema , P S Vijayashree , Nair Prashant , Husain Zakir , Sahu Diwyanshu , Mundkur Nirjhar , O'Reilly Eileen Mary
Published: May 2020

e16766

Background: Current therapy for PDAC is modestly effective. Therapy selection guidelines are typically limited to single aberrations and ignore relevant patient-specific omics. These alterations create patient-specific resistance pathways that cancer cells use to resist one-mutation one-drug Physician Choice therapies. Singula™ utilizes the novel Cellworks Omics Biology Model (CBM), which predicts patient-specific biomarker and phenotype response of a personalized diseased cell to drug agents, radiation and cell signaling. We test the hypothesis that Singula is a more accurate predictor of patient-specific therapy response to targeted agents compared to Physician Choice. Methods: The performance of the Singula Classifier of patient therapy response was evaluated in an independent retrospective cohort of N = 52 Stage I - IV PDAC patients aged 35-85, whose omics data were included in TCGA and ICGC. The accuracy of Singula was compared to the accuracy of prescribed therapies and clinical outcomes. Comparisons in the accuracy were enabled using McNemar’s test to account for the correlation between Singula and physician recommendations. Logistic regression was used to model complete response (CR) as a function of age, prescribed therapies, and Singula against non-response (NR). Likelihood ratio tests were performed to assess if Singula provides predictive information beyond prescribed therapy and age alone. Similar analyses were performed for progression-free survival (PFS) and overall survival (OS) using proportional hazards regression. Results: Singula is a superior predictor of CR compared to Physician Choice (McNemar’s χ2 = 26.0, p-value < 0.0001), with an overall accuracy of 94.2% (84.1%, 98.8%) compared to 40.4% (27.0%, 54.9%) for Physician Choice. In regressions, Singula (p = 0.0023) remained a significant predictor of CR, but prescribed therapy (p = 0.3885) and age (p = 0.1148) were nonsignificant. Singula was also the only significant predictor of PFS (p = 0.0002) and OS (p = 0.0096). For all 28 true negatives, alternative therapy selections with predicted response were generated. Conclusions: Singula is a superior predictor of PDAC response to therapy compared to Physician Choice. The Singula report can validate therapy selection decision, potentially increasing median PFS and OS and provides alternative therapy selections for non-responders. Prospective validation is needed. [Table: see text]
Therapeutic effect and safety of individualized chemotherapy combined with sequential immunotherapy based on BRCA1 mRNA expression level in the treatment of unresectable pancreatic cancer.
Authors: Du Juan , Zhu Linxi , Sha Huizi , Zou Zhengyun , Yu Lixia , Shen Jie , Kong Weiwei , Zhao Lianjun , Qiu Yudong , Liu Baorui
Published: May 2020

e16773

Background: Pancreatic cancer is a kind of digestive tumor with low incidence but high degree of malignancy. It is characterized by difficult in early detection and invasive metastasis. Together with high recurrence and metastasis rate after resection, the prognosis of pancreatic cancer is extremely poor. To explore the role of BRCA1 mRNA expression in the chemotherapy of unresectable pancreatic cancer and the synergistic effect of chemotherapy and immunotherapy, our center has carried out a clinical trial which focuses on individualized chemotherapy combined with sequential immunotherapy according to BRCA1 mRNA expression in the first-line treatment of unresectable pancreatic cancer. Methods: The expression of BRCA1 mRNA in tumor tissues of patients with pancreatic cancer was detected. According to the expression level, gemcitabine combined with nab-paclitaxel-based or gemcitabine combined with oxaliplatin-based biweekly chemotherapy combined with sequential GM-CSF and IL-2 immunotherapy was applied. Patients’ conditions and the efficacy and safety were assessed every 4 cycles. Results: A total of 25 patients were enrolled in the study. All of them were observed for toxic side effects and 24 of them were evaluated for efficacy. The median overall survival and median progression-free survival were 11.9 months and 6.3 months. The disease control rate was 91.7%, of which 37.5% (9/24) patients achieved partial remission (PR), 54.2% (13/24) patients achieved stable disease (SD) and 8.3% (2/24) patients were assessed as progressive disease(PD). Of the 15 patients with medium or high expression in BRCA1 mRNA, 7 achieved PR and 8 achieved SD. Of the 9 patients with low BRCA1 mRNA expression, 2 achieved PR, 5 achieved SD and 2 had PD. The proportion of eosinophils in the blood of some patients with good therapeutic effects was significantly higher than that before treatment. Hematological and non-hematological toxicity during the treatment were mostly grade 1~2. The two most common grade 3~4 adverse events were fever and thrombocytopenia. Conclusions: Our results suggest that individualized selection of chemotherapy combined with sequential immunotherapy according to BRCA1 mRNA expression level in the treatment of unresectable pancreatic cancer have curative effect and controllable adverse reactions. The improvement of treatment efficiency may be related to the activation of non-specific immune response.
A PK/PD mathematical model to forecast severe toxicities in pancreatic cancer patients treated with FOLFIRINOX regimen.
Authors: Deyme Laure , Gilabert Marine , Mineur Laurent , Toullec Clemence , Gasmi Mohamed , Ciccolini Joseph , Barbolosi Dominique , Gattacceca Florence
Published: May 2020

e16774

Background: FOLFIRINOX regimen is the most efficient treatment in pancreatic adenocarcinoma. However, this triple-therapy causes significant and dose-limiting toxic effects leading to empirical dose-reduction, postponement of the forthcoming courses and sometimes treatment discontinuation. Dose-limiting toxicities with FOLFIRINOX are mostly oxaliplatin-induced peripheral neuropathy (OIPN) and irinotecan-induced diarrhoea (IID). The first aim of our study was to establish dose-concentration-toxicity relationships for these two main ordinal toxicities. Second, we aimed to perform in silico simulations to define the optimal FOLFIRINOX administration protocol (i.e., dosing, scheduling, sequencing) for a maximal benefit to risk ratio. Methods: We performed a retrospective pharmacometric analysis from clinical data collected in three French institutes. Patients had all confirmed diagnosis of PDAC treated with FOLFIRINOX as first line regimen. Demographic characteristics, toxicity data and dosage modifications were collected. Two mathematical models connecting dose – concentration – toxicity (PKPD Tox model) were developed using Monolix2019 to describe both OIPN and IID. Results: Data from 75 patients (36 females/39 males) treated with FOLFIRINOX regimen between 2015-2018 and representing 566 courses were collected. Median age was 65.4 years (range 29-78). The performance status at the start of treatment was 0-1 for 70% of patients. The most frequent location of the tumor was pancreatic head (50%). 91% of patients were subject to empirical dose reduction during their treatment. Oxaliplatin doses were decreased in 258 courses and stopped in 66 courses. Irinotecan doses were decreased in 257 courses and stopped in 33 courses. Overall, 130 IID and 198 OIPN events were observed. From these data, two different PKPD Tox models were developed. The individual concentrations of SN38 (active metabolite of irinotecan) and oxaliplatin were simulated with population PK models, either home-built or taken from the literature. Concentrations were translated into adequate exposure via an interface model developed by our group. Exposure was finally related to a pharmacodynamic model to predict probabilities assigned to each grade of IID or OIPN. Conclusions: These PKPD Tox models help to predict dose-limiting toxicities upon FOLFIRINOX and are useful to select the administration protocol of FOLFIRINOX minimizing the occurrence probabilities of treatment-related neuropathy and diarrhoea, while maintaining efficacy.