bluuebunny/crossref_metadata_2025_split huggingface dataset:
Screening or symptoms? Colorectal cancer diagnosis in Uruguay.
Authors: Fontes Santiago , Berry Megan , Marín-Jiménez Ana , Sánchez Juan Carlos , Krygier Gabriel David , Cuello Mauricio 
Published: January 2023

71 Background: Colorectal cancer (CRC) remains a major health burden worldwide. Screening is employed due to its proven efficacy in reducing CRC incidence and mortality. In Uruguay, there is a longstanding National CRC screening program using fecal occult blood test (FOBT) as the preferred method. It is to be expected that patients with screen-detected CRC have better prognosis than those with symptoms due to earlier diagnosis and other favorable tumor/host characteristics. Beyond the well described earlier stage at diagnosis, other aspects have not been widely studied and data is sparse. An increasing proportion of CRC patients are diagnosed by screening rather than symptoms. Aim: We sought to establish and evaluate the correlation between clinicopathological features and TNM stage at diagnosis and diagnostic modality. Methods: A retrospective review of all newly diagnosed CRC patients from January 2008 to December 2021 was conducted by the authors. A total of 934 patients aged 50-80 years at diagnosis were included. Clinical, histological, diagnostic and treatment data was collected and findings were stratified and correlated according to screening detection vs symptomatic patients. Results: On one hand, 15% of patients had a positive FOBT leading up to their diagnosis. FOBT detected tumors presented a less advanced locoregional T-N staging (p = 0.001). Tumors were preferentially located in the proximal colon (33.1 vs 19.9%); p<0.001. Stage I CRC was more frequently detected in subjects with positive FOBT (14.2%) than in individuals with symptoms (5.9%); p = 0.002. Conversely, detection rates for stage IV CRC were 17.7% and 26.7% respectively; p = 0.002. A higher percentage of stage III screened patients underwent adjuvant chemotherapy when compared to their symptomatic counterparts (97.7 vs. 85.0 %, p = 0.016). On the other hand, 793 patients (85 %) were diagnosed after onset of signs or symptoms. There was a preponderance of advanced-stage disease (stages III–IV 36-27% respectively). The most common symptoms reported were change in bowel habits (52%), abdominal pain (47 %) and bleeding (45%). The most common overall sign was anemia. One hundred eighty-two patients (22.5%) required an emergency surgery mainly for obstructive colon cancer. Conclusions: Despite equal access to colorectal cancer screening, in Uruguay diagnosis after development of symptomatic cancer remains more common. FOBT detected cancers presented less advanced clinicopathological characteristics and differing management that potentially could be driving a more favorable outcome. Mode of detection is therefore an important indicator that should be taken into account when defining risk assessment in treatment decisions. These findings also support the need for continued improvement and recruitment of patients into screening programs. It must be the focus for future initiatives.
Phase II trial of maximal ablative irradiation because of encasement (MAIBE) for patients with potentially resectable locally advanced pancreatic cancer.
Authors: Reyngold Marsha , Alice Wei , O'Reilly Eileen Mary , D'Angelica Michael Ian , Drebin Jeffrey A. , Soares Kevin , Kingham T. Peter , Balachandran Vinod P. , Varghese Anna M. , Park Wungki , Khalil Danny , Yu Kenneth H. , Zinovoy Melissa , Cuaron John J , Hajj Carla , Romesser Paul Bernard , Wu Abraham Jing-Ching , Zhang Zhigang , Jarnagin William R. , Crane Christopher H. 
Published: January 2023

710 Background: For patients with localized but not immediately resectable pancreatic adenocarcinoma (PDAC), the role for local therapy remains undefined. Phase II MAIBE trial studied ablative radiation (A-RT) followed by consideration of surgery for patients with locally advanced pancreatic cancer (LAPC) who remain unresectable after induction chemotherapy. Methods: Participants with histologically confirmed PDAC judged unresectable by multidisciplinary review using NCCN definition after completing 3-6 months of mFOLFIRINOX (FFX) or Gemcitabine/Nab-paclitaxel (GN) were eligible. They received hypofractionated A-RT (either 67.5Gy in 15 fractions or 75Gy in 25 fractions based on anatomy) with concurrent capecitabine followed by consideration of resection within 1-3 months. Primary endpoints included resectability (80% power to detect resectability improvement from 15% in historical controls to 30% with α = 0.05) and overall survival (OS) from A-RT. Secondary endpoints included safety of surgical resection after ablative RT using 90-day Clavien-Dindo Classification of adverse events (AE). Results: Between 6/2018 and 4/2022, 47 eligible participants underwent A-RT. Median age was 67 (range, 50-80) years, 24 (51%) were male with a median tumor size of 3.95 (1.6 – 8.3) cm and CA19-9 of 92 ( < 1-1601) U/mL. Forty-four patients (94%) received at least 1 cycle of FFX with a median duration of chemotherapy (FFX or GN) of 3.5 months (1.0 – 9.4). Sixteen (34%) underwent a laparoscopy and 12 (26%) underwent a resection (Pancreaticoduodenectomy, N = 11; distal pancreatectomy, N = 1) at a median time of 3.2 months (1.9-16.9 months) from start of A-RT. The rate of resection satisfied our prespecified boundary of 11. R0 rate was 58.3%. Two-year OS from A-RT for the entire cohort was 38.9% (95% CI, 21.9 – 55.6%), including 37.1% (18.5 - 55.8%) in non-surgical and 39.4% (7.0- 72.1%) in surgical groups. There were no deaths within 90 days of surgery and 9 surgical AEs were recorded in 6 participants, including grade 1 (n = 1), grade 2 (n = 5), grade 3 (n = 2) and grade unknown (n = 1). Conclusions: In patients with LAPC and no metastatic disease after 3-6 months of chemotherapy, A-RT results in a favorable rate of resection without excess surgical toxicity. Promising 2-year OS rates were noted in both resected and non-resected patients. Clinical trial information: NCT03523312 .
A multi-institutional, single-arm, phase II trial of neoadjuvant modified-FOLFIRINOX for resectable pancreatic ductal adenocarcinoma.
Authors: Lee Choong-kun , Hwang Ho Kyoung , Jeung Hei-Cheul , Chon Hongjae , Park Hyung Soon , Kim Min Hwan , Kim Sung Hyun , Park Mi-Suk , Kang Chang Moo , Choi Hye Jin 
Published: January 2023

715 Background: Various peri-operative treatments have been tested to increase the survival of localized PDAC. Even with superior survival among various disease extent of PDAC, resectable PDAC still shows poor outcomes with surgery followed by adjuvant chemotherapy. We report the result of a multi-institutional phase II trial of modified-FOLFIRINOX as neoadjuvant treatment for resectable PDAC. Methods: Treatment naïve pts with histologically confirmed resectable PDAC were enrolled. Resectability was confirmed by both CT and MRI according to NCCN resectability criteria (no arterial tumor contact to celiac axis, SMA or CHA; no tumor contact with SMV or PV or ≤180° contact without vein contour irregularity) in multidisciplinary team meeting. Patients received oxaliplatin 85mg/m2 D1 + leucovorin 400mg/m2 D1 + irinotecan 150mg/m2 D1 + 5-FU 2,000mg/m2 46h continuous infusion, every other week for 6 cycles (12 weeks). Response assessments were performed every 6 weeks using the RECIST criteria version 1.1. Baseline MRI, PET-CT scan, and pre-surgery MRI after 6 cycles were mandatory. The primary endpoint was R0 resection rate. Secondary endpoints included survivals, ORR, safety, resection rate, and correlative biomarker exploration. (NCT05066802). Results: Total of 27 pts were enrolled between May 2020 and Feb 2022. Among total 27 pts, 24 pts underwent curative aim surgery after neoadjuvant treatment (resection rate 88.9%), and 23 pts showed R0 resection (23/27=85.2%), meeting the primary endpoint. Among 27 pts, 19 pts (70.4%) completed the neoadjuvant treatment per protocol. The reasons for neoadjuvant treatment discontinuation included progression of the disease (n=3, 11.1%) and pts withdrawal (n=5, 18.5%). Among 19 patients who underwent surgery per protocol, only one patient was R1 resected (R0 resection rate=94.7%). As of Sep 1, 2022 (median follow-up duration = 15.2 months) 6 pts recurred after surgery (6/19=31.6%). Median recur-free survival was 18.7 months (95%CI 13.6-NR) and median OS was not reached (95%CI 17.6-NR) for the per protocol treated pts. Treatment-related AE (≥G3) occurred in 10 pts (37.0%) including 7 (25.9%) with neutropenia G3-4. Conclusions: Three months of neoadjuvant mFOLFIRINOX was feasible and tolerable for resectable PDAC. Larger randomized trial is needed to validate the impact of neoadjuvant chemotherapy for resectable pancreatic cancer and to find subgroup of pts who would get benefit most from the neoadjuvant treatment. Post hoc genomic analyses with paired pre-neoadjuvant treatment and surgical tissues are ongoing. Clinical trial information: NCT05066802 .
Prediction of early treatment failure of second-line nal-iri/5-FU/FA in patients with advanced pancreatic adenocarcinoma (AIO-PAK-0216).
Authors: Karthaus Meinolf , Ansorge Nikolaus , Barmashenko Gleb , Burkart Christof , Decker Thomas , Ettrich Thomas Jens , Gerhardt Anke , Hoefling Sabine , Jacobasch Lutz , Koenigsmann Michael , Räth Sebastian , Schulte Markos , Schulte Nadine , Schwarzer Andreas , Siegler Gabriele Margareta , Waldschmidt Dirk , Lutz Manfred P. 
Published: January 2023

721 Background: Second-line Nal-Iri/5-Fluorouracil/Folinic Acid (Nal-Iri/5-FU/LV) increases overall survival of unselected patients (pts) with metastatic pancreatic ductal adenocarcinoma (PDAC) after gemcitabine-based therapy. It is unknown, which pts will likely benefit or could probably profit more from alternative approaches. Methods: In this prospective trial, 156 pts with locally advanced or metastatic PDAC were included for treatment with biweekly Nal-Iri/5-FU/LV (70 mg/m², 2.4 g/m², 400 mg/m²) after failure of 1st line chemotherapy with Gemcitabine/nab-Paclitaxel, with comprehensive evaluation of prior treatment characteristics, potential predictive factors, and quality of life. Primary end point is the correlation of time to treatment failure (TTF) of 1st and 2nd line therapy. Moreover, translational research was done to measure and evaluate biomarkers in blood and tumor tissue. Here, we explore patient characteristics in two subgroups with short or long treatment duration, with the aim to evaluate potential predictive factors for further analysis. Results: 139 (90%) of the 156 pts included between 03/2018 and 07/2021 in 40 German sites received medication. End of treatment is documented for 128 pts, with 5 still on treatment as of 05/2022 Mean (±SD) treatment duration was 15.5 weeks or 7.7±7.1 cycles (median 7 weeks; 5 cycles). 37 (25%) pts received ≥ 10 cycles. The median was used to separate two subgroups of short and long treatment duration (STD, ≤ 5 cycles, n=66 (52%) vs. LTD, > 5 cycles, n=62, (48%)). Reasons for treatment discontinuation clearly differed between the two subgroups: death in 9% vs. 3%, toxicity in 9% vs. 2%, unrelated medical condition in 12% vs. 2%, and progressive disease in 46% vs. 73%, respectively. Investigator´s decision was a reason for discontinuation in 6% vs. 5%. Pts with STD had a lower performance status (ECOG 1 or 2 in 74% vs. 52%, ECOG 0 in 20% vs. 44% in STD vs. LTD group), lower albumin levels (below normal in 36% vs. 24.2%) and were more likely to suffer from liver metastases (overall 82% vs. 66%). There were no relevant differences with regard to age, sex and tumor burden (number of metastases or CA19-9 levels). Conclusions: Early treatment discontinuation was primarily associated with patient-related factors such as low performance status, low albumin levels and comorbidities, characteristics which could be used to spare patients from treatment with an unfavorable risk-to-benefit ratio. In contrast, surrogate markers for tumor burden did not correlate with treatment success. Clinical trial information: NCT03468335 .
Using tumor growth rate to inform treatment efficacy in pancreatic adenocarcinoma: From the metastatic to the neoadjuvant setting.
Authors: LaRose Meredith , Yeh Celine , Zhou Mengxi , Sigel Keith Magnus , Jameson Gayle S. , White Ruth Aroon , Safyan Rachael A , Saenger Yvonne M. , Hecht Elizabeth , Chabot John A. , Schreibman Stephen M. , Fojo Antonio Tito , Manji Gulam Abbas , Von Hoff Daniel D. , Bates Susan Elaine 
Published: January 2023

726 Background: The development of new treatments in oncology is a long, costly, and, too often, unsuccessful process. Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials are needed. Methods: We used a mathematical model of tumor growth kinetics fit to serial radiographic tumor measurements or CA19-9 values to estimate rates of exponential tumor growth [g] and decay [d] during treatment for pancreatic ductal adenocarcinoma (PDAC). Results: We retrospectively collected and analyzed data from 2691 patients with stage III-IV PDAC who were enrolled in five clinical trials or were included in two large real-world data sets from Columbia University Irving Medical Center and Veterans Administration Medical Centers. Using log-rank comparison of Kaplan-Meier plots by quartile of g, we found that in patients with metastatic PDAC g correlates highly with overall (OS) and progression-free survival (PFS) (p<0.001), with slower g associated with improved survival in this population. Pairwise comparisons showed significantly slower median g in the experimental arm versus control arm in the pivotal trials analyzed (p<0.001). At the individual patient level, g was significantly faster for liver metastases as compared to primary pancreatic tumors and g consistently increased towards the end of therapy (often a threefold increase) suggesting development of chemoresistance. In addition to utility in the metastatic setting, a pilot analysis of data from a prospective study of patients treated with gemcitabine + docetaxel + capecitabine (GTX) in the neoadjuvant setting suggests that the emergence of a detectable g during neoadjuvant therapy may portend worse OS following surgery though sample size was small (n=45, median OS with detectable g 13.6 m v 33.1 without detectable g, p =0.35). Conclusions: We applied a tumor growth model to the data of over 2500 patients with PDAC and showed that g is inversely associated with survival in this population. Given the strong association between g and survival, g could be useful in clinical trials as an informative endpoint to expedite the assessment of novel therapies for the treatment of PDAC. Furthermore, g offers valuable patient-level data, including trends in resistance and variations in growth rate by metastatic disease site We plan to evaluate whether the emergence of g during neoadjuvant therapy should be considered a prompt to change treatment regimens.
Intra-arterial gemcitabine vs IV gemcitabine PK substudy in patients with locally advanced pancreatic cancer.
Authors: Zureikat Amer H. , Pishvaian Michael J. , Meredith Kenneth , Hatoum Hassan , Zervos Emmanuel E. , Nazemzadeh Reza , Novelli Paula M. , Tsobanoudis Alex , Agah Ramtin 
Published: January 2023

728 Background: Localized dual-balloon-mediated, intra-arterial delivery of Gemcitabine (IAG) directly into tumors/tissue can lead to higher local drug potency1. Furthermore, IAG may lead to decreased systemic drug concentration and associated side effects. In patients with Locally Advanced Pancreatic Cancer (LAPC), this approach is currently being tested in a contemporary Phase III clinical trial, TIGeR-PaC. Herein we report the results of a 10-patient PK analysis sub-study within TIGeR-PaC. Methods: We analyzed a total of 10 subjects from 5 sites who received intra-arterial gemcitabine with the RenovoCath dual balloon catheter at 1000mg/m2 over 20 minutes. The target treatment artery was either the celiac axis (n=5) or the superior mesenteric artery (n=5). Samples were drawn at T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion. At each timepoint, we collected 2mL of blood in heparinized tubing containing 25 mcg/mL of tetrahydrouridine. The blood samples were then centrifuged collect, freeze, and ship the plasma to a reference lab to perform a gemcitabine assay. The PK parameters for a single dose was estimated for Cmax, AUC, clearance, and distribution volume based on the terminal phase. These values are compared to historical data for intravenous gemcitabine (IVG) infusion at 1000mg/m2 over 30 minutes2. Results: At this time, data has been analyzed for 4 of 8 collected samples. We expect to complete collection and analysis of all 10 samples by November of 2022. We show results available so far; historical values for IVG are given as a reference point. The results suggest that IAG is associated with decreased systemic exposure of gemcitabine compared to IVG. Conclusions: Localized dual-balloon-mediated, intra-arterial delivery of gemcitabine can lead to decreased systemic levels of gemcitabine. This approach increased local potency and may be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 04:21 PM Abstract No. 392 . J Vasc Intervent Radiol 2019;30(3):S172. doi:10.1016/j.jvir.2018.12.467. 2. Chow ECY, Zirkelbach JF. Clinical Pharmacology and Biopharmaceutics Review(s) {209604Orig1s000}. FDA: Center for Drug Evaluation and Research. Clinical trial information: NCT03257033 . [Table: see text]
Interim analysis results of gut microbiota in patients with unresectable cholangiopancreatic cancer: SCRUM-Japan MONSTAR-SCREEN.
Authors: Tezuka Shun , Sakai Shunsuke , Yamashita Riu , Horasawa Satoshi , Fujisawa Takao , Sawada Kentaro , Yoshikawa Ayumu , Nakamura Yoshiaki , Umemoto Kumiko , Shibata Nobuhiro , Ohtsubo Koushiro , Itoh Shinji , Todaka Akiko , Sudo Kentaro , Furukawa Masayuki , Ikeda Masafumi , Morizane Chigusa , Ueno Makoto , Yoshino Takayuki 
Published: January 2023

733 Background: MONSTAR-SCREEN prospectively assessed the gut microbiota of 2000 patients (pts) with advanced solid cancer at 31 Japanese institutions. Here, we report the interim analysis results of the correlation between gut microbiota and the efficacy of first-line chemotherapy in pts with unresectable pancreatic cancer (PC) and bile tract cancer (BTC). Methods: We analyzed unresectable 205 PC and 83 BTC pts with clinical data as data cut-off on April 30, 2021, and 16S ribosome analysis results of stool samples. Among PC pts, 133 and 40 were treated with GnP (gemcitabine (GEM) plus nab-paclitaxel) and FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), respectively. Among BTC pts, 32 and 33 were treated with GC (GEM plus cisplatin) and GCS (GEM, cisplatin, plus S-1), respectively. Pts with an above-median overall survival (OS) were defined as long-term survivors (LTS), and those with below-median OS and OS events were defined as short-term survivors (STS). We compared the alpha diversity index (ADI) of LTS and STS, and identified potential microbial biomarkers of LTS, STS, responders, and non-responders to first-line chemotherapy according to RECIST version 1.1, by linear discriminant analysis effect size (LEfSe). In each cohort, the top three microbiota with linear discriminant analysis scores of ≥ 3.0 were considered significant. Results: The median OS of PC and BTC pts was 13.5 and 15.9 months, respectively. In PC pts, no significant difference was noted in the ADI between LTS (n=20) and STS (n=40). In BTC pts, the ADI of LTS (n=10) was significantly higher than that of STS (n=20) in the Shannon index. LEfSe analysis in PC pts revealed that Burkholderiales and Sutterellaceae were predominant in LTS, while Lactobacillaceae was, in STS. In PC pts, Brachyspiraceae and Erysipelotrichales were predominant in responders (n=67), while Enterococcaceae and Lactobacillaceae were, in non-responders (n=137). In BTC pts, Peptostreptococcaceae, Fusobacteriaceae, and Clostridiaceae in LTS; Cardiobacteriaceae, Prevotellaceae, and Actinobacteriota in responders (n=24); and Bacilli in non-responders (n=59) were overrepresented. Conclusions: This interim analysis identified potential biomarkers of the gut microbiota that may contribute to the prognosis and efficacy of chemotherapy in pts with unresectable PC and BTC. The results of this analysis will be validated in the primary analysis.
The divergent role of the GM-CSF/GM-CSFR signaling pathway in cholangiocarcinoma and pancreatic ductal adenocarcinoma.
Authors: Dave Yatee A. , Burchard Paul R. , Ruffolo Luis I. , Ullman Nicholas A. , Georger Mary , Jewell Rachel , Belt Brian A. , Linehan David 
Published: January 2023

736 Background: The granulocyte-macrophage colony-stimulating factor ligand and receptor (GM-CSF/GM-CSFR) pathway plays a multifaceted role in the setting of cancer, exerting an anti-tumorigenic or pro-tumorigenic effect depending on GM-CSF expression. In previous work, we and others have shown increased GM-CSF expression to correlate with poor prognosis in patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). We also demonstrated how GM-CSF neutralization leads to reduced tumor size in murine CCA models, in part due to inhibition of alternative macrophage polarization. Here, we explore the impact of blocking GM-CSFR signaling in CCA and PDAC, two immunologically cold tumors with poor prognoses. Methods: Immunohistochemistry (IHC) and digital quantification of staining was performed on tissue from a human PDAC and CCA databank. Murine F4/80+ bone marrow-derived macrophages were cultured in tumor-conditioned media (TCM) derived from PDAC (KP2) or CCA (URCCA4.3) cell lines, with and without anti-GM-CSFR antibody. Quantitative real time PCR (qRT-PCR) analysis was performed for gene expression. URCCA4.3 and a luciferase-labeled PDAC (KCKO) cell line were orthotopically implanted into Bc/BIL3 knockout (KO) mice which lack GM-CSFR and C57BL/6 mice. Mice implanted with URCCA4.3 were enrolled into vehicle or gemcitabine treatment groups. Mice implanted with KCKO were untreated. Tumor growth was monitored by ultrasonography or bioluminescence imaging. Results: Digital analysis of IHC staining for GM-CSFR in human PDAC tumors revealed low expression to be associated with improved overall survival (OS) and greater number of days to recurrence, while high levels were associated with worse OS and fewer days to recurrence (p<0.01). In addition, human CCA specimens had greater GM-CSFR expression compared to normal uninvolved liver (p<0.01). qRT-PCR analysis of RNA from bone marrow-derived macrophages exposed to either CCA or PDAC TCM demonstrated lower expression of genes associated with alternative macrophage polarization ( Arg1, Cd274, Pdcd1lg2) and chronic inflammation ( Ccl2, Ccl17, Irf4) (all p<0.01) in response to GM-CSFR blockade. GM-CSFR KO mice implanted with URCCA4.3 demonstrated no differences in tumor growth with or without chemotherapy, compared to wild-type controls. Similarly, KO mice implanted with an immunogenic PDAC cell line (KCKO) had no differences in tumor size compared to wild-type controls. Conclusions: GM-CSFR expression is prognostic in the setting of PDAC and elevated in human CCA compared to normal liver. In vitro, GM-CSFR blockade downregulated pro-tumor genes associated with immunosuppression and inflammation. However, complete disruption of GM-CSFR signaling reversed the efficacy generated with GM-CSF ligand neutralization, suggesting some signaling is required for inducing anti-tumor immune responses.