bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II study of ipilimumab and nivolumab with radiation in metastatic pancreatic adenocarcinoma.
Authors: Parikh Aparna , Wo Jennifer Yon-Li , Ryan David P. , Clark Jeffrey W. , Nipp Ryan David , Blaszkowsky Lawrence Scott , Weekes Colin D. , Van Seventer Emily , Ly Leilana , Foreman Bronwen , Corcoran Ryan Bruce , Hong Theodore S. 
Published: January 2019

391 Background: Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal cancer. Immunotherapy (IO) has shown minimal activity. In preclinical models, radiation (XRT) increases likelihood of response to IO via an abscopal effect where local tx (treatment) of a tumor leads to an antitumor response distantly, with synergy between XRT and dual checkpoint blockade. In this study, we assessed CTLA-4 and PD-1 blockade with XRT as a strategy to stimulate an immune response for patients (pts) with PDAC. Methods: In this open-label, single arm phase-2 study, we enrolled 25 metastatic PDAC pts in an exploratory cohort. Eligible pts had histologically-confirmed PDAC, ECOG PS 0-1, and progression on at least 1 line of tx. Tx consisted of Ipilimumab (1 mg/kg every 6 wks), Nivolumab (240 mg every 2 wks) and 3 fractions of 8 Gy of XRT at cycle 2. Tx continued until PD, discontinuation or withdrawal. Endpoints include Disease Control Rate (DCR), ORR, PFS, OS and safety. Radiological evaluations were every 3 months. Response was defined as disease control outside of the radiation field. We obtained serial tumor biopsies pre-tx, during checkpoint blockade alone and 2 weeks after XRT. Intention to treat analysis includes all pts receiving at least one dose of study tx. Results: 22 pts were enrolled and evaluable from 6/2017-6/2018, median age 60 years (32-75), 73% male and 100% MSS. DCR was 27% and ORR was 14% with 1 pt having a complete response. All responses were out of the radiation field. Median PFS was 76 days in the entire cohort; 163 days for pts with disease control vs 62.5 days for pts with PD or who came off study prior to initial imaging. 7 pts did not receive XRT due to clinical progression. Treatment-related adverse events (AEs) were reported in 12/22 pts (54.5%). 8/22 pts (36.4%) experienced grade ≥ 3 toxicities. Elevated lipase, lymphopenia, fatigue, hyperglycemia, mucositis and hepatitis were the most common AEs. 1/22 (4.5%) pt had a grade 5 AE possibly related to tx. Conclusions: Dual blockade of CTLA-4 and PD-1 with XRT is feasible and demonstrates promising activity in pts with metastatic PDAC. We will report the updated efficacy and safety data as well as outcomes from the correlative serial biopsies upon completion. Clinical trial information: NCT03104439.
Impact of adjuvant hepatic arterial chemoinfusion using high-dose 5-fluorouracil with systemic gemcitabine for pancreatic cancer: A propensity score–matched analysis.
Authors: Nakamura Kota , Sho Masayuki , Akahori Takahiro , Nagai Minako , Nakagawa Kenji , Takagi Tadataka , Ikeda Naoya , Tanaka Toshihiro , Nishiofuku Hideyuki , Kichikawa Kimihiko 
Published: January 2019

402 Background: The aim of this retrospective study was to evaluate the efficacy of adjuvant hepatic arterial infusion chemotherapy (HAI) using high-dose 5-fluorouracil with systemic gemcitabine on prognosis of resected pancreatic cancer. Methods: Between January 2006 and April 2016, 298 patients underwent elective pancreatic resection for resectable or borderline resectable pancreatic cancer at Nara Medical University Hospital. Patients who received adjuvant HAI plus systemic gemcitabine after surgery (HAI group) were compared with those who received systemic chemotherapy alone (control group). Patients were propensity score matched for age, sex, ASA score, CA19-9, NCCN resectability status, neoadjuvant treatment, surgical procedure, portal vein invasion, T stage, N stage, and margin status. Results: 224 patients with resectable or borderline resectable pancreatic cancer were enrolled in this study. 151 patients in the HAI group and 73 patients in the control group were included. Propensity score matching analysis was used to identify 63 well-balanced patients in each group for overall survival comparison. The estimate overall survival (OS) for patients treated with HAI was longer than patients without HAI in both the whole cohort (median OS, 54 vs. 24 months, respectively; P < 0.001) or matched cohort (median OS, 58 vs. 26 months, respectively; P = 0.003). The liver was only recurrence site in which significant decrease was observed in the HAI group compared to the control group ( P = 0.031). In the multivariate analysis, adjuvant chemotherapy without HAI were independently associated with worse outcome in the whole cohort. A total of 127 patients in the HAI group (84%) had completed the planned dose of HAI. The remaining 24 patients stopped treatment before the end of the planned cycle due to catheter-associated complications in 9 (6.0%) and development of liver abscess in 2 (1.3%). No treatment-related deaths occurred. Conclusions: The efficacy of hepatic arterial chemoinfusion as adjuvant treatment for resectable pancreatic cancer should be revisited.
The need for improvement in the management of fatigue, depression and pain in pancreatic cancer.
Authors: Westermann Amy , Matrisian Lynn McCormick , Rahib Lola 
Published: January 2019

429 Background: Pancreatic cancer (PC) and its treatment(s) results in symptom and side effect burden and can impact patient’s overall quality of life (QOL). Methods: Patient reported information on management of side effects and symptoms were collected using PanCAN’s Patient Registry (01/2016 – 07/2018). Results: Patient reported information on side effects, pain and depression is detailed in the table. Side effects: 94% reported fatigue and 8% reported taking anti-fatigue medication. 72% reported nausea or vomiting during treatment and 83% reported taking anti-nausea medication. Pain: Of the 90% of patients who reported pain related to PC, 27% did not take pain medication, 47% visited the ER and 32% were hospitalized due to pain. Depression: Of the 83% of users reported feeling depressed during PC, 46% were diagnosed with depression, 37% prescribed anti-depressant, and 48% did not see a therapist. Conclusions: Nausea was reported as most managed. Fatigue, pain and depression were generally unmanaged. ER visits and hospitalizations due to pain were frequently reported. An improvement in the management of these side effects and symptoms is needed as it can affect patient’s ability to tolerate treatment, improve overall QOL, and may lower overall healthcare costs. [Table: see text]
Phase II study of ibrutinib in advanced carcinoid and pancreatic neuroendocrine tumors.
Authors: Al-Toubah Taymeyah E. , Valone Tiffany , Schell Michael J. , Strosberg Jonathan R. 
Published: January 2019

434 Background: Ibrutinib is an orally administered, inhibitor of Bruton’s tyrosine kinase (Btk). Preclinical data suggest that mast cells are recruited with neuroendocrine tumors (NETs) where they remodel the stroma and stimulate angiogenesis, driving macroscopic tumor expansion. Ibrutinib inhibits mast cell degranulation, and has been associated with regression of a mouse insulinoma model. Methods: A prospective, phase II trial evaluated patients with advanced GI/lung NETs and pNETs who had evidence of progression within 12 months of study entry on at least one prior therapy. Patients received ibrutinib 560mg daily until unacceptable toxicity, progression of disease, or withdrawal of consent. Primary endpoint was objective response rate. Results: 20 patients were enrolled on protocol from November 2015 – December 2017 (15 carcinoid and five pNETs). No patients experienced objective response. Median PFS was 3.1 months. A total of 43 drug related AEs were captured as probably or definitely associated with ibrutinib. Five patients experienced probably or definitely related grade 3 AEs and one patient experienced a probably related grade 4 AE. Five patients discontinued treatment prior to radiographic assessment. Conclusions: Ibrutinib does not show significant evidence of activity when compared to other agents (e.g. Everolimus) in well-differentiated gastroenteropancreatic and lung NETs. Clinical trial information: 02575300.
Adjuvant HIPEC in patients with colon cancer at high risk of peritoneal metastases: Primary outcome of the COLOPEC multicenter randomized trial.
Authors: Klaver Charlotte Emma Louise , Wisselink Daniel D , Punt Cornelis J. A. , Snaebjornsson Petur , Crezee Johannes , Aalbers Arend , Bemelman Willem A , Brandt Alexandra , Bremers Andre , Burger Jacobus W.A. , van Grevenstein Wilhelmina M.U. , Hemmer Patrick H.J. , de Hingh Ignace H.J.T. , Kok Niels , Tuynman Jurriaan , Wiezer Marinus J. , de Wilt Johannes H. W. , Dijkgraaf Marcel G , Tanis Pieter J. ,   Dutch Colorectal Cancer Group
Published: January 2019

482 Background: Patients with T4 or perforated colon cancer are at high risk (~25%) of peritoneal metastases (PM). Sensitivity of imaging modalities for PM is limited and the majority of patients is diagnosed in a palliative setting. This provides a rationale for adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC). In this study, the effectiveness of adjuvant HIPEC in reducing the risk of PM was determined. Methods: In this multicenter trial, patients with T4 (either cT4 or pT4, N0-2, M0) or perforated colon cancer, who underwent curative resection were randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy or to adjuvant systemic chemotherapy alone (1:1). Adjuvant HIPEC with oxaliplatin was performed simultaneously (9%) or within five-eight weeks (91%) after the primary tumor resection. Patients without evidence of recurrent disease at 18 months based on CT imaging underwent diagnostic laparoscopy in both arms. The primary endpoint was PM free survival (PMFS) at 18 months using Kaplan Meier analysis. Results: Between April 2015 and January 2017, 204 patients were randomized: 102 in the control arm (0 drop-outs), 102 in the experimental arm (two drop-outs). Surgical exploration at the start of the HIPEC procedure at five-eight weeks postoperatively revealed metastases in 11 patients (PM in 9/11) in the experimental arm, and adjuvant HIPEC was not applied. Adjuvant systemic chemotherapy was administered in 89/100 eligible patients after median 6 weeks (IQR 5-7) in the control arm and in 84/89 after 10 weeks (IQR 9-12) in the experimental arm. PM rate after completion of 18 months follow-up was 22/102 and 18/100, respectively. In the ITT analysis no difference in 18 months PMFS was observed: 77% (control) versus 81% (experimental), HR 0.836 (0.489-1.428)). Also, no differences were observed in 18 months DFS (HR 1.016 (0.646-1.598)) and OS (HR 1.139 (0.532-2.439)). One patient developed encapsulating peritoneal sclerosis after HIPEC. Conclusions: Adjuvant HIPEC with oxaliplatin for patients with T4 or perforated colon cancer does not result in improved 18 months PMFS. Long-term results have to be awaited to assess the role of HIPEC in the adjuvant setting. Clinical trial information: NCT02231086.
Molecular comparison of primary colorectal cancer (pCRC) with peritoneal metastases (PM).
Authors: Stein Matthew K , Williard Forrest W , Tsao Miriam , Deschner Benjamin , Dickson Paxton Vandiver , Glazer Evan Scott , Martin Michael Gary , Deneve Jeremiah Lee 
Published: January 2019

498 Background: PM from CRC are associated with poor outcomes; however, molecular differences are not defined. Methods: We compared tumor profiles of pCRC and PM patients (pts) from Caris Life Sciences. Testing included next-generation sequencing (NGS) of 592 genes, immunohistochemistry (IHC), copy number variants (CNV), microsatellite instability (MSI) and tumor mutational burden (TMB). Mutations were termed pathogenic (PATH) or variants of undetermined significance (VUS). TMB in mutations/Mb (MMB) was compared. Results: 617 pCRC and 348 PM pts had similar gender (55% male) and age (median 59). 232 pCRC were left-sided (LS), 189 right-sided (RS), 147 rectum (R) and 49 not otherwise specified (NOS); PM were 45 RS, 29 LS, 22 R and 252 NOS. For pts with IHC testing, expression was increased in PM in TOPO1 (62% v. 52%, p < 0.01), ERCC1 (27% v. 18%, p < 0.01) and MLH1 (96% v. 92%, p < 0.05) and decreased in PD-1 (36% v. 65%, p < 0.01), TOP2A (76% v. 100%, p < 0.01) and PTEN (64% v. 72%, p < 0.05). By sidedness, LS PM were more frequently TOP01 and PD-L1 and less commonly MGMT positive compared to pCRC. PTEN IHC was higher in R pCRC than PM. 7 CNVs were increased in PM ( ADGR2A2, CCND1, ELL, FGF3, FGF4, JAK3 and PDGFRB) and FLT3 CNVs were decreased. MYC CNVs were more common in RS PM compared to pCRC. No difference was seen in PM and pCRC PATHs in KRAS, BRAF, SMAD2, SMAD4, PTEN. PM had more PATHs in GNAS (8% v. 1%, p < 0.01) while pCRC PATHs were increased in APC (76% v. 48%, p < 0.01), TP53 (72% v. 53%, p < 0.01), ARID1A (29% v. 12%, p < 0.05), PIK3CA (22% v. 15%, p < 0.05) and FBXW7 (13% v. 7%, p < 0.01). LS PM had increased FLCN PATHs (12% v. 2%, p < 0.01); R PM had more PATHs in KMT2D (20% v. 1%, p < 0.01) and RNF43 (13% vs. 3%, p < 0.05). VUS were increased in 39/592 (7%) genes for PM compared to pCRC. No MSI or fusion difference was seen. 53% pCRC (median = 8) pts had TMB ≥8 MMB compared to 43% PMs (median = 7; p = 0.03); no TMB difference was seen for LS, RS or R subgroups. Conclusions: Compared to pCRC, PM had more PATHs in GNAS and less in classic CRC markers APC and TP53. While TMB was generally lower in PM, differences in IHC expression, CNV and VUSs may serve as biomarkers for PM requiring further study.
Patient and disease characteristics of colorectal cancer in a cohort of young patients.
Authors: Hanayneh Wissam , George Thomas J. , Read Thomas , Tan Sanda , Iqbal Atif , Allegra Carmen Joseph , Parekh Hiral D. 
Published: January 2019

513 Background: Despite effective screening for colorectal cancer (CRC), the incidence has been steadily rising in younger patients; the etiology for this phenomenon remains elusive. Methods: CRC patients diagnosed at < 50 years of age (UF institutional registry 2000-2017) constituted the IRB approved study cohort. Results: Young CRC patients (n = 286) comprised 16% of total CRC patients (n = 1806) treated at our institution. (See table for demographics and tumor characteristics.) The median age at diagnosis was 45 years (range 17-50) with two-thirds diagnosed at age 40-50 (n-212, 74%) and 182 patients (63.6%) had a history of tobacco and/or alcohol use. The majority of patients (73.1%) had a left-sided tumor and 35% (n = 99) had stage 4 disease at presentation. The median time to diagnosis from onset of first symptoms was 90 days. DNA mismatch repair gene deficiencies (dMMR) and/or microsatellite instability (MSI) was tested in 172 patients (60.1%); 18 (10.5%) had MSI-H or dMMR tumors and 11 of those had confirmed Lynch syndrome through. Next generation sequencing (NGS, n = 71) or mutational analysis (n =79) was performed on 52.4%; most common mutation was KRAS (40.7%, n = 61) followed by TP53 (7.33%; n = 11) and PIK3CA (5.33%; n = 8). BRAF V600E was seen in five patients and another two had BRAF variant. Conclusions: Our results reveal that the majority of younger CRC were 40-50 years age group with a female preponderance. Advanced disease at diagnosis and longer median time to diagnosis should prompt educational efforts regarding appropriate screening and timely diagnostic investigation in this patient cohort. [Table: see text]
Outcomes by tumor location in patients with metastatic colorectal cancer (mCRC) treated with regorafenib (REG): Final analysis from the prospective, observational CORRELATE study.
Authors: Ducreux Michel , Petersen Lone Nørgård , Öhler Leopold , Bergamo Francesca , Metges Jean-Philippe , de Groot Jan Willem , Wang Chao-Yuan , García-Paredes Beatriz , Dochy Emmanuelle , Fiala-Buskies Sabine , Cervantes Andres , O'Connor Juan Manuel , Falcone Alfredo ,   CORRELATE Investigators
Published: January 2019

539 Background: The anatomical location of the primary tumor has been associated with different prognosis and outcomes in mCRC. REG significantly improved overall survival (OS) versus placebo in patients with mCRC who progressed on standard therapies in phase 3 trials. We report the final results of outcomes in patients with mCRC with left-sided (L) or right-sided (R) primary tumors who were treated with REG in the real-world CORRELATE study. Methods: CORRELATE (NCT02042144) was a prospective, observational study designed to characterize the safety and effectiveness of REG in patients previously treated with approved therapies and for whom the decision to treat with REG was made by the treating physician according to the local health authority label. Patients with tumor location unknown or tumors in both regions were excluded (n = 62). OS was analyzed using the Kaplan–Meier method. Results: Overall, 975 patients were included in the analysis: L = 768 (79%) and R = 207 (21%). Most patients were ECOG PS 0–1 (L: 86%; R: 87%). Median time from initial diagnosis and from diagnosis of metastatic disease to REG treatment was slightly longer in L versus R tumors (34 vs 30 months and 27 vs 23 months, respectively). A higher proportion of patients with L versus R tumors, respectively, had prior radiotherapy (34% vs 15%) and a lower proportion had a partial colectomy (44% vs 75%). Both groups received a median of three prior regimens. REG treatment duration was similar in the two groups (median duration: L 2.6 months vs R 2.3 months), as was median progression-free survival (95% CI): 2.8 months (2.6, 2.9) for L tumors versus 2.7 months (2.5, 3.1) for R tumors. Median OS (95% CI) was 7.4 months (6.7, 8.0) for L tumors versus 8.2 months (6.6, 9.3) for R tumors; one-year OS rates were 32% versus 34%, respectively. Conclusions: Results from this observational study suggest that OS is similar in patients with L and R tumors treated with REG. Clinical trial information: NCT02042144.
Occurrence of irreversible sinusoidal obstruction syndrome during adjuvant chemotherapy for colorectal cancer using oxaliplatin: A multi-center study.
Authors: Yamada Takeshi , Koda Keiji , Yoshida Hiroshi , Tanakaya Kohji , Ishibashi Keiichiro , Yoshimatsu Kazuhiko , Kosugi Chihiro , Tanaka Soichi , Hara Keisuke , Tsubaki Masahiro , Nakajima Hideo , Oya Masatoshi , Ishida Hideyuki 
Published: January 2019

546 Background: Oxaliplatin reduces the recurrence rate after curative surgery for stage III colorectal cancer. However, it can cause hepatic sinusoidal obstruction syndrome (SOS), an adverse effect that creates morbidity after liver resection for recurrence. SOS has conventionally been diagnosed by liver biopsy, which is invasive. We have reported that a 10% increase in splenic volume (SV) indicates SOS (J Surg Oncol 2017). In this multi-center study, we measured SV to evaluate SOS caused by adjuvant chemotherapy. Methods: This multi-center study included the participants of the FACOS study, which included patients with Stage III colon cancer. Participants received 12 cycles of mFOLFOX6 or eight cycles of XELOX as adjuvant chemotherapy. We used multi-detector raw CT to measure SV three times; before surgery, on completion of adjuvant chemotherapy, and 1-year after completing adjuvant chemotherapy. CT images were taken in 5-mm slices. SV was calculated by using a volume calculator SYNAPSE VINCENT v3.0(Fujifilm, Japan). Results: The FACOS study included 130 patients, 16.9% of whom discontinued treatment. The mean relative dose intensity (RDI) of oxaliplatin was 80.3%. Grade 3 neutropenia, thrombocytopenia, and neuropathy were observed in 28.5%, 6.2%, and 4.6% of patients, respectively. The 3 year DFS was 82.2%. We analyzed data of 75 patients (57.7%) for whom the three CT studies were available. SV on completing chemotherapy (median 181 cm3) and SV 1-year after completing chemotherapy (141 cm3) were significantly higher than that before surgery (128 cm3) (P < 0.001). SV increased by more than 10% after chemotherapy in 72% and was still increased 1 year after chemotherapy in 51% of patients. Conclusions: In our previous single center study, SV had increased in 84% on completing chemotherapy and was still increased in 47% 1 year after completing chemotherapy. Adjuvant chemotherapy without oxaliplatin induced SV increases in only 20% of patients on completing chemotherapy. Thus, these results are reproducible and show the potential of oxaliplatin to induce SOS. Oxaliplatin frequently induces SOS and this SOS persists for over 1 year in half of affected patients. Clinical trial information: UMIN000005427.
Circulating tumor derived cell-free DNA (ctDNA) to predict recurrence of metastatic colorectal cancer (mCRC) following curative intent surgery or radiation: Interim results.
Authors: Esquivel Mikaela , Chee Bryant , Shih Brandon , Zhang Li , Corvera Carlos U. , Hirose Kenzo , Nakakura Eric K. , Van Loon Katherine , Raymond Victoria M. , Dix Daniel , Odegaard Justin , Atreya Chloe Evelyn 
Published: January 2019

552 Background: Over half of patients (pts) with oligometastatic CRC treated with definitive surgery or radiotherapy experience cancer recurrence. Early detection of ctDNA could identify high risk pts for additional intervention to eliminate micrometastatic disease. Here we report interim results of a prospective study aiming to determine ctDNA detection rates using a sensitive multigene assay and to correlate post-procedure ctDNA detection with radiographic mCRC recurrence. Methods: Pts with mCRC intending to undergo a curative intent procedure were prospectively recruited at a single site. ctDNA was collected pre-procedure, 3 weeks (wks) post-procedure, and at multiple follow-up timepoints. ctDNA detection utilizing a multi-gene sequencing panel (Guardant Health) included somatic variant and epigenetic assessments. A novel variant classifier was applied to differentiate tumor derived versus non-tumor derived alterations. A Simon’s two-stage design with planned interim analysis to assess 3wk post-procedure ctDNA detection rate was employed. Results: Of 25 pts enrolled, 21 (84%) had evaluable paired pre- and post-procedure samples. In these 21 pts, the 3 wks post-procedure sample was collected after surgery (N = 20) or radiation (N = 1) to address liver (N = 17), lung (N = 3), or ovarian (N = 1) metastases ± colon resection (N = 6). ctDNA was detected (+) in 15/21 (71%) pre- and 11/21 (52%) post-procedure samples. ctDNA was (+) in 8/12 (67%) pre- and 8/17 (47%) post-procedure samples with carcinoembryonic antigen < 5 ng/ml. Conclusions: In this interim analysis of pts with mCRC undergoing curative intent procedures, the post-procedure ctDNA detection rate was 52%. The similarity between the observed post-procedure ctDNA detection and expected recurrence rate suggests promise for recurrence prediction using this approach. Given post-procedure ctDNA was (+) in > 3 pts, the study will continue to enroll, and pts are being followed for future correlation of ctDNA with radiographic recurrence. [Table: see text]