bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of the preoperative waiting period on the survival in patients with clinical stage II / III gastric cancer.
Authors: Kenichiro Furukawa , Makuuchi Rie , Fujiya Keiichi , Nishiwaki Noriyuki , Omori Hayato , Kaji Sanae , Tanizawa Yutaka , Bando Etsuro , Kawamura Taiichi , Koseki Yusuke , Asaoka Raito , Nakamura Kenichi , Waki Yuhei , Irino Tomoyuki , Terashima Masanori 
Published: January 2019

27 Background: Although prolonged preoperative waiting period (PWP) for gastric cancer (GC) may influence the prognosis, the relationship between PWP and survival outcome has not been elucidated. The aim of this study is to identify the impact of PWP on survival in patients with clinical stage (cStage) II / III GC. Methods: A total of 483 patients who underwent surgery for cStage II / III GC according to Japanese classification of GC, 14th edition, between January 2002 and December 2012 were included. The patients who underwent endoscopic submucosal dissection or neoadjuvant chemotherapy, or who had multiple cancer, special histological types of tumor, or urgent symptoms were excluded. We defined PWP as the period from the date of endoscopy for initial diagnose to that of surgery. Patients were divided into two groups according to PWP; short waiting period group (SWPG, PWP ≤ 60 days, n = 357) and long waiting period group (LWPG, PWP > 60 days, n = 126). Survival outcomes were compared between the groups and multivariate analysis for overall survival (OS) was conducted to identify independent prognostic factors. Results: The median PWP was 49 (21-323) days. In LWPG, patients were significantly older (P = 0.001) and had more comorbidities (P = 0.042) than those in SWPG. Preoperative lymph node status was significantly lower in LWPG (P = 0.031), although there were no differences in tumor depth and cStage between the groups. There was no difference in OS between the groups (5-year OS, SWPG: 61.0%, LWPG: 63.2%, P = 0.612). Multivariate analysis for OS identified age, BMI, histological type, and cStage as independent prognostic factors. Conclusions: Preoperative waiting period appears to have no influence on survival in patients with cStage II / III GC.
Using circulating tumor DNA (ctDNA) to predict surgical outcome after neoadjuvant chemoradiation for locally advanced pancreatic cancer (LAPC).
Authors: McDuff Susan , Parikh Aparna Raj , Hazar-Rethinam Mehlika , Zheng Hui , Van Seventer Emily , Nadres Brandon , Ryan David P. , Weekes Colin D. , Clark Jeffrey W. , Fernandez-del Castillo Carlos , Ferrone Cristina , Lillemoe Keith D , Murphy Janet E. , Goyal Lipika , Zhu Andrew X. , Wo Jennifer Yon-Li , Blaszkowsky Lawrence Scott , Allen Jill N. , Corcoran Ryan Bruce , Hong Theodore S. 
Published: January 2019

272 Background: Curative resection is possible following neoadjuvant treatment for LAPC, yet there is no method to identify patients beforehand who will have a favorable surgical outcome. This study was designed to assess the ability of ctDNA measured during neoadjuvant chemoradiation (CRT) to predict surgical outcome for LAPC. Methods: 38 LAPC pts were enrolled at our institution between 10/2015 - 5/2017. Pts received neoadjuvant FOLFIRINOX followed by CRT: either short-course ( n = 9, 25 Gy/5 fractions), or long-course ( n = 29, 50.4 Gy/28 fractions). Serum ctDNA was measured at baseline, weekly during CRT, and preoperatively. After extracting DNA from plasma, a tumor mutation specific droplet digital PCR assay was used to detect the fraction of ctDNA molecules. The following clinical and pathologic outcomes were noted: CA19-9, CEA, RECIST score, tumor grade, T stage, tumor regression grade (TRG), R-resection status, pathologically involved lymph nodes, LVI, and PNI. Results: The median age of the cohort was 67 years (range 42-85 years). Following CRT, 32 (84%) were operable. The overall R0-node negative (R0-NN) resection rate was 66% for the entire cohort. The rate of R0-NN resection was significantly higher among patients with an undetectable preoperative ctDNA ( n= 16) compared to those with a detectable ( n= 22) preoperative ctDNA (88% R0-NN vs 50% R0-NN, respectively, Fisher’s exact p = 0.036). On univariate logistic regression, only ctDNA status was significantly associated with R0-NN resection (p = 0.025), whereas preoperative RECIST score, CA19-9, and CEA were not associated. On multivariable logistic regression, ctDNA remained a borderline significant predictor for R0-NN resection when controlling for CA19-9 ( p = 0.058). For patients who received surgery, the ctDNA allele fraction was significantly correlated with TRG ( Pearson R = 0.399, p = 0.024). Conclusions: Undetectable preoperative ctDNA is associated with R0-NN surgical outcome in a cohort of patients treated with neoadjuvant CRT for LAPC. This approach is worthy of further study to establish guidelines for incorporating ctDNA into clinic with the goal of improving patient selection for surgery.
Effect of stereotactic radiation (SBRT) on survival in a preclinical model of spontaneous pancreatic cancer with induction gemcitabine/nab-paclitaxel.
Authors: Taniguchi Cullen M. , Molkentine Jessica , Fujimoto Tara N , Colbert Lauren Elizabeth , Deorukhkar Amit , Herman Joseph M. 
Published: January 2019

273 Background: There are no useful preclinical models that resemble relevant fractionated radiation, such as SBRT, with relevant chemotherapy. Most preclinical studies use a single fraction of radiation to large fields, causing significant toxicity and/or insufficient dose which leads to accelerated repopulation and worsened outcomes. Here, we employ mice with spontaneous pancreatic tumors, and treat them in a preclinical trial utilizing gemcitabine/nab-paclitaxel +/-SBRT. Methods: Mice with an activated KRas (G12D) allele and heterozygous for p53 expression only in the pancreas (KPC) were created and spontaneous tumors were diagnosed via weekly palpation and ultrasound. Mice with single tumors that were between 3-7mm at diagnosis were sequentially randomized to received either no treatment, gemcitabine/nab-paclitaxel x 2 weeks, or gemcitabine/nab-paclitaxel x 2 weeks followed by 8Gy x 5 daily fractions of SBRT to the pancreatic tumor. SBRT was delivered using X-RAD 225Cx (Precision X-Ray, Inc) small animal irradiator under image guidance by cone beam micro CT using AP/PA technique with a 10mm collimator. Every mouse was subjected to necropsy and a cause of death assigned. Tumor growth was monitored by small animal ultrasound. Kaplan-Meier survival analysis was performed to assess efficacy of treatments. Results: A total of 40 mice were enrolled with 12 receiving chemotherapy alone, 13 receiving chemotherapy +SBRT and 15 mice had no further treatment. The addition of induction chemotherapy improves lifespan compared to untreated mice. The addition of SBRT further improved survival. Causes of death in untreated animals of the gemcitabine/nab-paclitaxel group were largely from local progression, whereas the addition of SBRT provided local control causing most of the mice in this cohort to die from metastatic progression. Conclusions: SBRT improves survival when added to gem/nab-paclitaxel in a preclinical model, which may reflect favorable biology for this approach. Our novel system employs similar SBRT fields and doses, and may thus be useful for the evaluation of other chemotherapeutic regimens with SBRT.
Expression of immune genes and a signature of PD-1 inhibition resistance in basal-like pancreatic adenocarcinoma (PDAC) subtypes.
Authors: Joseph Ranjit , Collins Kyla , Bortone Dante S. , Vincent Benjamin Garrett , Yeh Jen Jen , McRee Autumn Jackson 
Published: January 2019

277 Background: PDAC is a lethal disease with poor survival even when detected at an early stage. Recurrence rates after surgical resection remain high. Recently, two distinct molecular subtypes of PDAC (basal-like and classical) have been identified with basal-like tumors demonstrating inferior outcomes. We hypothesize that differences in tumor immunogenicity may contribute to this aggressive biology and predict response to immune checkpoint inhibitors. Methods: RNA sequencing was performed on formalin-fixed paraffin embedded samples of 60 resected PDAC patients. We evaluated previously published immune gene expression signatures comprised of 1400 genes and used a single sample classifier to determine molecular subtypes. Results: Table 1 summarizes patient characteristics in our cohort. There were 35 classical and 25 basal-like tumors. PFS was significantly shorter in patients with basal-like compared to classical subtypes (9 vs 15 mo, p = 0.006). In a multivariable model with molecular subtype, lymph node and margin status, subtype was the only independent predictor of PFS (p=0.028). Unsupervised clustering identified two distinct immune groups that were associated with molecular subtypes (p=0.038) with higher expression of immune genes in basal-like tumors. Basal-like tumors were significantly associated with an immunosuppressive signature (p<0.001) and a signature associated with non-response to PD-1 inhibition in melanoma (p=0.001). Conclusions: This is the first study to show that basal-like pancreatic cancers are associated with increased immune gene expression and may help explain their inferior prognosis. We hypothesize that this reflects an increase in immunosuppressive cells in basal-like tumors that may predict decreased response to immune check point inhibitors. [Table: see text]
Lymphopenia and outcomes of patients with unresectable hepatocellular carcinoma treated with radiotherapy.
Authors: Ng Sweet Ping , Liu Amy , Tao Randa , Holliday Emma Brey , Brownlee Zachary , Kaseb Ahmed Omar , Raghav Kanwal Pratap Singh , Vauthey Jean-Nicolas , Minsky Bruce D. , Herman Joseph M. , Das Prajnan , Taniguchi Cullen M. , Krishnan Sunil , Crane Christopher H. , Hong Theodore S. , Mohan Radhe , Koay Eugene Jon 
Published: January 2019

278 Background: The immune system plays a crucial role in cancer surveillance. Lymphopenia during cancer treatment portends poor prognosis. Here, we aim to quantify lymphocyte count changes during radiotherapy (RT) for patients with hepatocellular carcinoma (HCC) treated with proton or photon RT. Methods: Patients with HCC treated with definitive RT from 2006 to 2016 with ≥3 months follow-up were studied. Patient characteristics, tumor features, treatment specifics were recorded. Serial absolute lymphocyte counts (ALC) were collected and graded according to CTCAE v4.0. Overall survival (OS) and distant metastasis free survival (DMFS) were analysed using the Kaplan-Meier method. To investigate difference in ALC between treatment modalities, we performed a paired cohort analysis (15 proton and 15 photon cases, matched to treatment volume). Results: 110 patients were studied. Median age was 67 years. 70% of the cohort had Child-Pugh A5 liver disease and 54% had venous tumor thrombosis (VTT). 75 (68%) had photon RT and 35 (32%) had proton RT. Median OS was 13 months. Overall, there was a 60% drop in ALC during RT. Splenic volume correlated with Grade 3 (G3) lymphopenia (p < 0.0001). Pre-treatment ALC and splenic volume did not correlate with OS or DMFS. Patients who had G3 lymphopenia during RT had poorer DMFS (14 vs 34 months, p = 0.006) and OS (16 vs 34 months, p = 0.015) than their counterparts. Those who received proton RT had a higher ALC nadir (0.56 vs 0.40 k/ul, p = 0.041), lower rate of ALC drop (0.07 vs 0.05 k/ul/day) and better OS (30 vs 22 months) than those who had photon RT. Paired cohort dosimetric analyses revealed that there was a significantly higher low dose volume in the photon group (V1Gy and V10Gy, p < 0.0001 for both; V5Gy, p = 0.002). Higher volume of low dose bath correlated with lower ALC (r = -0.34, p = 0.06 for V1Gy; r = -0.44, p = 0.01 for V5Gy; r = -0.51, p = 0.004 for V10Gy). Splenic irradiation dose correlated with ALC nadir, and proton cases had significantly less splenic dose (p < 0.0001). Conclusions: G3 lymphopenia during RT portends poorer outcomes for patients with HCC. Protons may mitigate RT-induced lymphopenia. An ongoing phase III trial will compare proton and photon RT for HCC to determine the effect on OS.
Germline BRCA1/2, PALB2, and ATM mutations in 3,030 patients with pancreatic adenocarcinoma: Survival analysis of carriers and noncarriers.
Authors: Kasi Pashtoon Murtaza , Couch Fergus , Bamlet William R , Hu Chunling , Hart Steven , Polley Eric , Petersen Gloria M. , McWilliams Robert R. 
Published: January 2019

280 Background: Patients with pancreatic adenocarcinoma (PDAC) can have mutations in breast cancer associated genes ( BRCA1/2) and other homologous recombination (HR) pathway genes. The therapeutic significance of these mutations for PDAC patients is not yet established. We performed a comprehensive survival analysis of 3,030 unselected PDAC patients comparing non-carriers and carriers of BRCA1/2, PALB2, and ATM mutations. Methods: We analyzed germline DNA samples and outcomes from confirmed PDAC patients recruited from 1999-2014 into the Mayo Clinic SPORE in Pancreatic Cancer registry. A total of 3,046 genomic DNA samples were analyzed by next generation sequencing. All pathogenic variants were validated by Sanger sequencing. Survival analysis of PDAC patients with and without BRCA1, BRCA2, PALB2, or ATM germline mutations was performed using the Kaplan-Meier method and log-rank tests. Hazard ratios (HR) were calculated using Cox proportional hazard modeling adjusted for co-variates including age, sex, and stage. A p-value < 0.05 was considered statistically significant. Pre- and post-FOLFIRINOX eras were defined as before and after June 1, 2011. Results: A total of 139 (4.6%) patients were noted to have deleterious mutations in BRCA1, BRCA2, PALB2, or ATM genes. After exclusion of patients with missing data, final analysis was restricted to 2,452 PDAC patients. Overall survival was slightly better (14.2 months versus 11.3 months) in patients with mutations as compared to those without mutations, although this finding was not statistically significant (p = 0.07). When stratified by FOLFIRINOX era, 40 patients with these mutations in the post-FOLFIRINOX era had better outcomes than 668 non-carriers (adjusted HR 0.62; 95% CI 0.43-0.89; p = 0.0062). Conclusions: Deleterious germline BRCA1/2, PALB2, and ATM mutations were seen in approximately 5% of patients with PDAC. Post-FOLFIRINOX era patients with these mutations had improved outcomes, possibly secondary to exposure to DNA-damaging chemotherapies. Germline screening of PDAC patients and development of trials incorporating this information (e.g., PARP inhibitors) has potential value for PDAC patients.
A study of pelareorep in combination with pembrolizumab and chemotherapy in patients (pts) with relapsed metastatic adenocarcinoma of the pancreas (MAP).
Authors: Mahalingam Devalingam , Fountzilas Christos , Moseley Jennifer L. , Noronha Nicole , Cheetham Karol , Dzugalo Adrian , Nuovo Gerard , Gutierrez Andres , Arora Sukeshi Patel 
Published: January 2019

283 Background: Pelareorep (REOLYSIN) is a immuno-oncolytic virus (IOV) that induces an inflamed tumor phenotype secondary to viral infection of cancer cells. In combination with chemotherapy, it achieves 1 & 2 year-survival rates of 46% & 24% in MAP pts, respectively. Tumor analysis from pts showed reovirus protein replication, T-cell infiltration and upregulation of PD-L1. Similarly, the combination of pelareorep with anti-PD-1 antibody documented survival benefit in a pre-clinical model. We hypothesized that pelareorep in combination with chemo and pembrolizumab in pts with MAP would be clinically efficacious. Methods: A phase 1b study enrolled MAP pts who progressed after first line treatment. Pts received pelareorep (4.5 x 10 10TCID 50 IV, D1 & D2), plus pembrolizumab (2mg/kg IV, D8) plus either 1)5-FU (LV (200 mg/m2 /5-FU 200 mg /m2 IV bolus, 5-FU 1200mg/m2 continuous IV infusion D1) or 2) gemcitabine (1000 mg/m2 IV, D1), or 3) irinotecan (125 mg/m2 IV, D1) q3w, until disease progression/unacceptable toxicity. The primary endpoint was safety. Secondary objectives included tumor response & evaluation for reovirus replication/immune analysis. Results: 11 pts were enrolled with pelareorep, pembrolizumab and gem (n = 6), 5-FU (n = 3), or iri (n = 2). Most common grade 1 or 2 TEAEs include: fever (73%), headache (55%), chills (46%), dehydration (36%), fatigue (27%) and anemia (27%). One pt (gem arm), transient Gr 2 increased transaminases was reported on two occasions. Grade 3 or 4 TEAEs occurred in 8 pts (73%): abdominal pain, anemia, arthralgias, biliary obstruction, chills, DVT, diarrhea, fever, hyperglycemia, leukopenia, myalgias, nausea, neutropenia, pulmonary emboli, urinary tract infection and vomiting. Of the 5 efficacy evaluable pts, one had PR (13.8 m duration) and 2 SD (lasting 126 and 277 days). Eight died secondary to PD. On-treatment biopsy show reovirus infection in cancer cells and immune infiltrates. Conclusions: The combination therapy showed manageable safety profiles and antitumor activity in previously treated MAP pts. Further evaluation of anti-tumor activity of pelareorep and anti-PD-1 antibody ± chemotherapy combos is planned. Clinical trial information: NCT02620423.
A first-in-human phase I study of sEphB4-HSA (sEphB4) with expansion in hepatocellular (HCC) and cholangiocarcinoma (CCA).
Authors: Thomas Jacob Stephen , Lenz Heinz-Josef , Iqbal Syma , Tsao-Wei Denice D , Barzi Afsaneh , Duddalwar Vinay , Cole Sarah , Rehman Rabia , Menendez Xiomara , Krasnoperov Valery , Liu Ren , Feng Qingru , Gill Parkash S. , El-Khoueiry Anthony B. 
Published: January 2019

285 Background: EphrinB4, a receptor kinase, is associated with stage and survival in epithelial cancers. sEphB4 is a fusion protein of soluble EphB4 and albumin. sEphB4 binds to EphrinB2, a protein expressed in tumor cells and vessels, and blocks bidirectional signaling. sEphB4 downregulates the PI3K/AKT/mTOR pathway, inhibits angiogenesis, and promotes recruitment of cytotoxic T cells and NK cells. MTD was not reached during dose escalation. The RP2D was 10 mg/Kg weekly. Here we report the results of the expansion cohorts in HCC and CCA. Methods: The study evaluated the safety, PK, PD and efficacy of sEphB4 in pts with advanced solid tumors in a 3+3 design with expansion at the RP2D in 7 solid tumors including HCC and CCA. Pts received sEphB4 10 mg/kg IV weekly in 28-day cycles. Eligibility included ECOG 0-1, Child-Pugh score ≤ 7, platelets > 50,000, AST/ALT ≤ 3xULN, serum bilirubin ≤ 1.5mg/dL and no uncontrolled hypertension. Results: 29 pts were treated: 17 HCC and 12 biliary cancers (8 CCA and 4 gallbladder). Median age was 63(25-77). ECOG PS was 1 in 76%. Median prior regimens were 1 (0-6) for HCC and 2 (1-3) for biliary cancers. 2 HCC pts had prior liver transplantation, 9 had prior anti PD-1 therapy and 2 had Child-Pugh score of B7. Median number of cycles was 4 (1-21) in HCC and 2 (1-17) in CCA. No grade 4 treatment-related adverse events (TRAE). Grade 3 TRAE were hypertension (41%) and fatigue, headache, neutropenia all in 1 pt each. Disease progression was the most common reason for treatment discontinuation. Median PFS in months was 5.0 (3.0-7.5) in HCC and 3.0 (1.6-9.2) in CCA. Median OS in months was 27.1 (4.4-27.1) in HCC and 12.0 (3.0-28.2) in CCA. Disease control rate was 70% in HCC and 42% in CCA including 1 PR in HCC. In HCC pts, 5/5 with 3+ EphrinB2 expression in tumor had PR or SD ≥ 6 months. Only 1/4 pts with ≤2+ expression had SD ≥ 4 months. 3/3 pts with HCC showed an increase in T cell infiltration, and decrease in pS6 (PI3K pathway activity) on post-treatment biopsy. Conclusions: sEphB4 has a manageable safety profile with preliminary evidence of anti-tumor activity in pretreated pts with HCC and biliary cancers. Several trials combining sEphB4-HSA with cytotoxic chemotherapy or immunotherapy are ongoing. Clinical trial information: NCT01642342.
Clinical significance of monitoring KRAS in tissue and serum of pancreatic cancer patients.
Authors: Watanabe Fumiaki , Suzuki Koichi , Ishikawa Hideki , Endo Yuhei , Ichida Kosuke , Takayama Yuji , Fukui Taro , Kakizawa Nao , Kasahara Naoya , Kato Takaharu , Noda Hiroshi , Rikiyama Toshiki 
Published: January 2019

286 Background: KRAS monitoring provides valuable information for early diagnosis and prediction of treatment outcome in colorectal cancer. KRAS mutation is observed in only half of colon cancer patients, whereas it is detected in 90% of pancreatic cancer patients. Therefore, investigating tumor DNA in serum by KRAS monitoring may be even more valuable in pancreatic cancer patients. In this study, we elucidated the clinical significance of KRAS monitoring in pancreatic cancer patients during treatment. Methods: KRAS in tumor tissues was analyzed for mutations by Scorpion ARMS or RASKET in 69 patients with pancreatic tumors. KRAS in serum was analyzed for mutations (G12D, G12V, G12C, G12A, G12S, G12R, G13D, Q61L, and Q61H) using droplet digital polymerase chain reaction in 58 patients who underwent the curative surgery (N = 39) or the chemotherapy (N = 19) and who had KRAS mutation in their tissues. Results: KRAS mutation in tumor tissues was detected in 62 of 69 patients (92.5%). These 62 patients showed significantly poorer prognosis (3years overall survival; 43.9%) than the seven patients without mutation (p = 0.03), who were all alive. Monitoring of KRAS in serum revealed KRAS mutation in 22 of 58 patients (37.9%). In patients who underwent the chemotherapy (N = 19), 2years OS of patients who detected KRAS mutation in serum (N = 9) was 0% and them which not detected it (N = 10) was 46.7% (p = 0.01). And in the curative resection group (N = 39), we detected KRAS mutations in serum among recurrent patients after surgery, but did not detect them among non-recurrent patients. Conclusions: KRAS mutation in serum could be a valuable predictive and prognostic biomarker in pancreatic cancer patients. Additionally, assessment of KRAS in tumor tissues may provide information about individual tumor biology. So, monitoring KRAS status of patients with pancreatic cancer may be useful of the treatment strategy.