bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effectiveness of peptide receptor radionuclide therapy for neuroendocrine neoplasms: A multi-institutional registry study with prospective follow-up.
Authors: Hörsch Dieter ,   AG PRRT Germany
Published: March 2020

4033 Background: Peptide receptor radionuclide therapy targets somatostatin receptors expressed on well differentiated neuroendocrine neoplasms. Retrospective monocentric studies indicate that peptide receptor radionuclide therapy is an effective treatment for patients with neuroendocrine neoplasms. Methods: We initiated a multi-institutional, prospective and board reviewed registry study for patients treated with peptide receptor radionuclide therapy. 450 patients were included and followed for a mean of 24.4 months. Patients were treated with Lutetium-177 (54%), Yttrium-90 (17%) or both radionuclides (29%). Primary neuroendocrine neoplasms were derived of pancreas (38%), small bowel 30%), unknown primary (19%), lung (4%) and colorectum (3,5%). Most neuroendocrine neoplasms were well differentiated with a proliferation rate below 20% in 54% and were pretreated by 1 or more therapies in 73%. Results: Overall survival of all patients from the beginning of therapy was 59 months in median. Median survival depended on radionuclides used (Yttrium-90: 38 months; Lutetium-177: not reached; both: 58 months), proliferation rate (G1: median not reached; G2: 58 months; G3: 33 months; unknown: 55 months) and origin of primary tumors (pancreas: 53 months; small bowel: not reached; unknown primary: 47 months; lung: 38 months) but not upon number of previous therapies. Median progression-free survival measured from last cycle of therapy accounted to 41 months for all patients. Progression-free survival of pancreatic neuroendocrine neoplasms was 39 months in median. Similar results were obtained for neuroendocrine neoplasms of unknown primary with a median of 38 months whereas neuroendocrine neoplasm of small bowel were progression-free for a median of 51 months. Side effects like G3-G4 nephrotoxicity or hematological function were observed in 0.2% and 2% of patients. Conclusions: Peptide receptor radionuclide therapy is effective for patients with G1-G2 neuroendocrine tumors irrespective of previous therapies with a survival advantage of several years compared to other therapies and only minor side effects.
Interim safety and efficacy analysis of a phase II, randomized study of GVAX pancreas and CRS-207 immunotherapy in patients with metastatic pancreatic cancer.
Authors: Le Dung T. , Wang-Gillam Andrea , Picozzi Vincent J. , Greten Tim F. , Crocenzi Todd S. , Springett Gregory M. , Morse Michael , Zeh Herbert , Cohen Deirdre Jill , Fine Robert Lance , Onners Beth , Uram Jennifer N. , Murphy Aimee , Skoble Justin , Lemmens Ed , Grous John J. , Dubensky Thomas , Brockstedt Dirk G. , Jaffee Elizabeth M. 
Published: March 2020

4040^ Background: GVAX is composed of GM-CSF-secreting allogeneic pancreas cancer cell lines and administered with low-dose cyclophosphamide (CY) to inhibit regulatory T cells. In prior studies, GVAX induced mesothelin-specific T cell responses that correlated with survival. CRS-207 is a live-attenuated Listeria monocytogenes engineered to express human mesothelin. CRS-207 stimulates potent innate and adaptive immunity and has shown synergy with GVAX in mouse tumor models. Anecdotal survival benefit was observed in the CRS-207 phase I study in patients who received prior GVAX. Methods: Patients were enrolled with metastatic pancreatic ductal adenocarcinoma (PDA) who received or refused ≥ 1 prior chemotherapy, had ECOG ≤ 1 and adequate organ function. Patients were randomized 2:1 to receive 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B) every 3 weeks. Clinically stable patients were offered additional 20-week courses. The primary endpoint was comparison of OS between treatment arms. Secondary endpoints were to evaluate safety, clinical and immune responses. Results: 90 patients were treated (Arm A: 61, Arm B: 29). As of Jan 2013, 27 patients completed 1 course (A: 24, B: 3) and 17 patients (A: 15, B: 2) initiated a 2nd course. Median age was 63. Median number of prior regimens was 3. No treatment-related serious adverse events (SAEs) or unexpected toxicities were observed. The most frequent Grade (G) 3/4 related toxicities were fever, lymphopenia, hypophosphatemia, elevated liver enzymes, and fatigue following CRS-207 in <5% of subjects. Of 51 patients evaluated post-treatment, 34% had stable disease in Arm A vs. 19% in Arm B. OS for all patients treated was 6 months in Arm A vs. 3.4 months in Arm B (two-sided, p=0.0114). Conclusions: Combined CY/GVAX pancreas and CRS-207 was generally well-tolerated with no treatment-related SAEs or unexpected G3/4 toxicities. The significant difference in OS between treatment arms met the criteria for early stopping. This indicates that the combination immunotherapy may extend OS for metastatic PDA patients with minimal toxicity and should continue to be developed as an effective therapy. Clinical trial information: NCT01417000.
Pimasertib plus gemcitabine in metastatic pancreatic adenocarcinoma: Results of a safety run-in part of a phase II trial.
Authors: Verslype Chris , Hammel Pascal , Hidalgo Manuel , Macarulla Teresa , Garcia-Carbonero Rocio , André Thierry , Van Den Eynde Marc , Saez Berta Laquente , Milella Michele , Raymond Eric , Faivre Thea , Milner Alvin , Tarabaric Dolores , Locatelli Giuseppe , Richter Oliver von , Laffranchi Bernard , Van Cutsem Eric 
Published: March 2020

4041 Background: Activating MAPK pathway mutations (predominantly RAS) occur with a high incidence in metastatic pancreatic adenocarcinoma (mPaCa). Pimasertib is a MEK1/2 inhibitor with potent activity in cell lines and xenografts with an activated MAPK pathway. This two-part trial in patients (pts) with mPaCa comprises a dose-escalation safety run-in and a randomized phase II part (EudraCT 2009-011992-61). We defined the maximum tolerated dose (MTD), safety, pharmacokinetics (PK) and antitumor activity of two pimasertib dosing schedules (S), and the recommended phase II dose (RP2D). Methods: Dose-escalation (3+3 design) in two dosing S of oral pimasertib: once-daily (qd) - 5 days on, 2 days off (S1); and twice-daily (bid) - continuous (S2) combined with the standard dose of gemcitabine (gem). Results: 53 pts (median age 61 years and ECOG performance status 0-1) have been treated at six dose levels in S1 (15 to 120 mg qd) and at 60 and 75 mg bid in S2. MTDs were defined as 120 mg qd and 75 mg bid. Two pts had a dose-limiting toxicity (DLT) in the DLT observation period: a grade (G) 3 confusion with ataxia and disorientation at 60 mg bid and a G4 suicidal ideation at 75 mg bid. G3-4 adverse events (AEs) in >5% of pts were: neutropenia (32%), thrombocytopenia (25%), asthenia (19%), dyspnea (9%), transaminitis (9%), anemia (8%), and diarrhea, pulmonary embolism, pulmonary sepsis (6% each). Most common AEs were asthenia (70%), ocular AEs (68%), skin rash (62%), nausea (58%), diarrhea (58%), peripheral edema (51%), thrombocytopenia (49%), vomiting (45%), mucositis (43%), neutropenia (38%), decreased appetite (36%) and anemia (34%). The main ocular AE was serous retinal detachment (58%); manageable retinal vein occlusion occurred in five pts. PK data were comparable to pimasertib monotherapy and published gem data. Partial responses were noted in 10 pts and stabilisation ≥3 months in 13 pts. Hot spot mutations in genes activating the MAPK and PI3K/AKT pathway and correlation with clinical outcome are being investigated. Conclusions: Pimasertib MTDs were reached. The RP2D was defined as 60 mg bid. PK was dose proportional and associated with target inhibition. Sustained responses were seen in both dosing schedules. Clinical trial information: 2009-011992-61.
The impact of diabetes mellitus and metformin on survival of patients with advanced pancreatic cancer receiving chemotherapy.
Authors: Oh Do-Youn , Choi Younak , Kim Tae-Yong , Lee Kyung-Hun , Han Sae-Won , Im Seock-Ah , Kim Tae-You , Bang Yung-Jue 
Published: March 2020

4044 Background: A causal relationship between diabetes mellitus (DM) and pancreatic cancer (PC) is well established. However, in patients with advanced PC (APC) who receive palliative chemotherapy, the impact of DM on prognosis is unclear. Methods: Between 2003 and 2010, we enrolled consecutive patients with APC, all recipients of palliative chemotherapy, with the provision that DM disease status could be properly defined. Enrollees were stratified by diagnosis, in accordance with 2010 DM criteria (AHA/ADA). DM at least 2 years' duration prior to diagnosis of APC qualified as remote-onset DM (vs recent-onset). Clinical characteristics and outcomes were then analyzed. Results: Of the 349 enrollees with APC, 183 (52.4%) had DM. In patients with DM, 160 had DM at the time APC was diagnosed (remote onset, 87; recent onset, 73); and the remaining 23 developed DM during the course of APC treatment. Ultimately, 73.2% (134/183) of DM patients received antidiabetic medication (metformin (56), sulfonylurea (62), insulin (43)). By multivariate analysis, cancer extent (HR, 1.792; p < 0.001) and weight loss during chemotherapy (HR, 1.270; p = 0.08) were associated with diminished overall survival (OS), whereas a diagnosis of DM (HR, 0.788; p = 0.05) conferred a positive effect on OS ( OS 8.4 months in DM patients vs 7.5 months in non-DM patients, p = 0.04). Among DM patients, recent-onset DM trended toward prolonged OS, compared with remote-onset/subsequent DM (9.8 months vs. 7.9 months, respectively; HR, 0.789; p = 0.142). Neither antidiabetic medication in general nor sulfonylurea or insulin specifically affected OS. However, recipients of metformin survived longer than non-recipients (HR, 0.693; 95% CI, 0.492-0.977; p = 0.036). Relative to the APC cohort overall including non-DM patients, metformin conferred better survival as well (11.0 months vs. 7.8 months, HR 0.712, p = 0.067), given similar baseline clinical characteristics. Conclusions: In patients with APC receiving palliative chemotherapy, recent-onset DM (within 2 years of APC diagnosis) and metformin treatment are positive prognosticators, associated with prolonged OS.
A network meta-analysis (NMA) of randomized controlled trials (RCT) of chemotherapy regimens for metastatic pancreatic cancer (mPC).
Authors: Gresham Gillian , Gill Sharlene , Wells George A , Jonker Derek J. 
Published: March 2020

4050 Background: Recent RCTs suggest a survival benefit for combination therapy in mPC compared to gemcitabine alone. Such combinations include FOLFIRINOX and gemcitabine plus nab-paclitaxel (G+nab-P). Survival and safety outcomes of these regimens were analyzed using gemcitabine as the reference comparator. Methods: Systematic review and NMA included data from reported phase III RCTs meeting quality standards and compared chemotherapy treatment to gemcitabine for mPC between 2000 and 2013. Excluded were trials assessing locally advanced pancreatic cancer. Following inter-trial heterogeneity assessment (patient characteristics, trial methodologies, treatment protocols), Bayesian NMAs were conducted for primary (overall survival [OS]) and secondary (progression free survival [PFS]) outcomes, overall response rate [ORR], and safety. Results: 27 studies were included involving 10 429 patients and 18 different treatments. No significant heterogeneity was observed between trials. When indirectly compared, FOLFIRINOX, PEFG and G+nab-P were top ranked for OS, PFS and ORR (Table). Comparing FOLFIRINOX and G +nab-P, there was no significant difference in odds ratios (OR) for febrile neutropenia, diarrhea or sensory neuropathy. FOLFIRINOX caused more gr3-4 neutropenia (OR 1.85 (95%Cl 1.1-3.4),p<0.05), and G+nab-P trended more gr3-4 fatigue (OR 2.03 95% Cl 0.95-3.8). Conclusions: Survival and safety outcomes were comparable amongst the three regimens identified from this network meta-analysis for mPC. FOLFIRINOX tended towards a greater survival benefit over G+nab-P and PEFG although comparisons did not reach statistical significance.Head-to-head trials between FOLFIRINOX, G+nab-P and PEFG are needed to further compare the survival benefits and safety profiles of these treatments. [Table: see text]
Identifying targetable pathways in pancreatic cancer from endoscopic ultrasound-guided fine-needle aspirates (EUS/FNA): Providing a personalized approach to targeted therapy.
Authors: Wang-Gillam Andrea , Wani Sachin , Langley Emma J. , Gao Feng , Murad Faris , Mullady Daniel , Early Dayna S , Edmundowicz Steven Alphonse , Linehan David , Kuller Anne , Jain Anjali , Kim Phillip Sangwook , Singh Sharat , Azar Riad 
Published: March 2020

4051 Background: Targeted therapy trials in pancreatic cancer patients have either failed or, at most, provided only marginal benefit. Identification of activated key signaling pathways would allow the optimal selection of patients for kinase inhibitor trials. Hence, we launched a study to profile targetable pathways from EUS/FNA samples using an ultrasensitive multiplexed protein microarray platform (CEER, Prometheus). Methods: Patients who underwent routine diagnostic FNA for a suspicious lesion in the pancreas underwent two dedicated passes for CEER profiling of the following phosphorylated (activated) key molecules: HER1, HER2, HER3, c-met, IGF-IR, PI3K, AKT, MEK, ERK, and other signaling proteins. Results: Of 100 participants, final cytology results were: 73 carcinomas, 8 indeterminate, 13 negative, and 5 neuroendocrine. Pathway activation was heterogeneous in patients with carcinoma. Among 61 pancreatic cancer patients with adequate HER evaluation, a high prevalence of HER3 activation (62%) was observed, and concomitant activation of two or more HER pathways was seen in 52% of patients. In particular, activation of HER2 and HER3 was noted in 23% of carcinoma patients. High concordance of HER, PI3K and AKT activation was seen. Conclusions: Our study confirmed the feasibility of profiling targetable pathways from FNA samples. Furthermore, it illustrates highly variable and concomitant pathway activation among pancreatic cancer patients, suggesting the feasibility of a personalized approach to targeted therapy. Future trials will need to be designed to explore the clinical benefit of combinations of HER-targeted agents in defined subsets of pancreatic cancer patients, and further evaluation of the HER3 pathway is especially warranted. An analysis of pathway interactions and prognostic effects is in progress. [Table: see text]
MicroRNA biomarkers in whole blood for detection of pancreatic cancer.
Authors: Schultz Nicolai Aagaard , Dehlendorff Christian , Jensen Benny Vittrup , Bjerregaard Jon K. , Nielsen Kaspar , Bojesen Stig Egil , Calatayud Dan , Nielsen Svend Erik , Yilmaz Mette K. N. , Hollander Niels Henrik , Andersen Klaus Kaae , Johansen Julia S. 
Published: March 2020

4052 Background: There is a great need for biomarkers for early diagnosis of patients with pancreatic cancer (PC) to improve their poor prognosis. The aims were (1) to describe differences in miRNA expression in whole blood between patients with PC, healthy subjects (HS) and patients with chronic pancreatitis (CP); and (2) to identify panels of miRNAs for early diagnosis of PC. Methods: Case-control study. 409 patients with PC, 33 patients with other periampullary cancers (PAC) and 25 patients with CP were included prospectively in the Danish BIOPAC biomarker study. 312 blood donors were included as HS. MiRNA expressions in pretreatment 2.5 ml whole blood samples collected in PAXgene RNA tubes were investigated in three independent cohorts: “Discovery Study” (PC n=143, CP n=18, HS n=69); “Training Study” (PC n=180, HS n=199); and “Validation Study” (PC n=86, PAC n=33, CP n=7, HS n=44). TaqMan Human MicroRNA assay was used to screen 754 miRNAs in the “Discovery Study”. Fluidigm BioMark PCR System was used in the “Training Study” (38 miRNAs) and “Validation Study” (13 miRNAs). Results: The “Discovery Study” demonstrated that 38 miRNAs (out of a total of 754 miRNAs) in whole blood were significantly deregulated between patients with PC and controls. These miRNAs were tested in the “Training Study” and two diagnostic indexes were constructed including 4 miRNAs in bPANmiRC index I (= miR-150 + miR-636 – miR-145 – miR-223) or 10 miRNAs in bPANmiRC index II (= 6.9275 – 0.2134xmiR-122 – 0.3560xmiR-34a – 0.8577xmiR-145 + 1.0043xmiR-636 – 0.6725xmiR-223 + 0.7018xmiR-26b – 0.3233xmiR-885.5p + 1.1304xmiR-150 – 0.2204xmiR-126* - 0.1730xmiR-505) (AUC 0.86/0.93, sensitivity 85%/85% and specificity 64%/85%). Conclusions: We identified two diagnostic indexes, using 4 or 10 miRNAs in peripheral whole blood, with a potential clinical value in the evaluation of patients with uncharacteristic symptoms to identify PC at an early stage.
Prognostic value of an immune score combining intra- and peritumoral T-cell subset density in patients with pancreatic adenocarcinoma.
Authors: Turcotte Simon , McNicoll Yannic , Soucy Genevieve , Gaboury Louis , Lapointe Real W. , Vandenbroucke-Menu Franck 
Published: March 2020

4060 Background: Immune scoring based on T-cell subsets and density can add prognostic value to conventional TNM staging for patients with solid tumors, but limited data are available for pancreatic adenocarcinoma. Methods: Using tissue microarrays, CD3, CD4, CD8, CD45RO, and FOXP3 T-cells were quantified by immunohistochemistry in the intratumoral (IT) compartment and peritumoral (PT) parenchyma of 111 consecutively resected specimens. T-cell counts were correlated with patient overall survival, disease-free survival, and time to recurrence (OS, DFS, TTR) by Cox regression, controlling for clinicopathological factors. An immune score (IS) based on IT CD4 T-cell count > median, PT CD8 T-cell count ≤ median, and IT/PT CD3 T-cell ratio >1, grouped patients into high, intermediate, or low categories if all 3, 1 to 2, or none of these immune features were present, respectively. Results: Median follow-up time was 20 months, and 85% of patients either died or recurred during the study period. By univariate analysis, PT CD8 T-cell count was associated with shorter OS (p=0.02), whereas both IT CD4 T-cell count and IT/PT CD3 T-cell ratio were associated with longer OS (p=0.01 and p=0.05, respectively). Alone, none of these immune features predicted TTR. Combined into an IS, patients in the high (n=23), intermediate (n=60), or low (n=23) categories had significantly different OS (respective medians 30, 17, and 13 months, log-rank p=0.01), DFS (28, 16, and 12 months, p=0.01), and TTR (21, 14, and 10 months, p=0.02). By multivariate analysis, the association between IS and clinical outcomes was independent of tumor size, extra-pancreatic invasion, and nodal metastases (TNM staging). The IS discriminated outcomes among patients with nodal metastases (n=80), such that node-positive patients with a high IS had a median survival similar to node-negative patients (30 and 33 months, p=0.7). FOXP3 and CD45RO T-cell counts did not appear to add prognostic value to the IS. Conclusions: An immune score that combines specific T-cell location and density may have prognostic value in patients with resected pancreatic adenocarcinoma, independently from pathologic features currently used for staging.
A phase II trial of definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) in advanced esophageal cancer (KDOG 0501-P2).
Authors: Higuchi Katsuhiko , Komori Shouko , Tanabe Satoshi , Katada Chikatoshi , Azuma Mizutomo , Ishiyama Hiromichi , Sasaki Tohru , Ishido Kenji , Katada Natsuya , Hayakawa Kazushige , Koizumi Wasaburo ,   Kitasato Digestive Disease & Oncology Group
Published: March 2020

4070 Background: Our previous phase I study (Radiother Oncol 2008,87:398) provided evidence that definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) was tolerable and active in patients with advanced esophageal cancer (AEC). This phase II study was conducted to confirm the efficacy and toxicity of DCF-R in AEC. Methods: Patients with previously untreated carcinoma of the thoracic esophagus who had T4 tumors, M1 lymph-node metastasis, or both received an infusion of docetaxel (35 mg/m2) and an infusion of cisplatin (40 mg/m2) on day 1 and a continuous infusion of 5-fluorouracil (400mg/m2/day) on days 1-5, every 2 weeks, plus concurrent radiation (RT). The total RT dose was initially 61.2, but was lowered to multiple-field irradiation with 50.4 Gy to decrease esophagitis and late toxicity. Consequently, the number of cycles of DCF administered during RT was modified from 4 to 3. After DCF-R, patients received at least 2 cycles of DCF (docetaxel 40 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and 5-fluorouracil 600 mg/m2on days 1-5, every 4 weeks). The primary endpoint was the clinical complete response rate (cCRR). Secondary endpoints were response rate (RR), progression free survival (PFS), overall survival, and safety. Results: 42 patients (36 men, 6 women) were enrolled. The median age was 62 years (range: 46-75). PS 0/1/2 was 14/25/3. TNM classification T4M0/non-T4M1LYM/T4M1LYM was 20/12/10. The total scheduled dose of RT 61.2Gy /50.4Gy was 12/30 patients. The RR was 90.5% and the cCRR was 52.4% (95% CI:37.3-67.5%). As of January 2013, the median PFS was 11.1 months and the median survival time was 23.1 months. Grade 3 or higher major toxicities comprised leukopenia (71.4%), neutropenia (57.2%), anemia (16.7%), febrile neutropenia (38.1%), anorexia (31.0%), and esophagitis (28.6%). There was one treatment-related death caused by aspiration pneumonia. Grade 3 or higher late toxicities comprised one pericardial effusion (Grade 4), one case of esophagitis (Grade 3), and one case of thoracic aortic aneurysm (Grade 3). Conclusions: DCF-R frequently caused myelosuppression, but was highly active and suggested be a promising regimen in AEC. Clinical trial information: 000002029.