bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of the T and N stage in the American Joint Committee on Cancer (AJCC) 8th edition staging system for pancreatic cancer with curative resection.
Authors: Todaka Akiko , Fukutomi Akira , Furuta Mitsuhiro , Shirasu Hiromichi , Kawahira Masahiro , Kawakami Takeshi , Yoshida Yukio , Kawai Sadayuki , Hamauchi Satoshi , Tsushima Takahiro , Yokota Tomoya , Machida Nozomu , Yamazaki Kentaro , Onozawa Yusuke , Yasui Hirofumi
Published: January 2019

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Background: The 8th edition of the AJCC staging system for pancreatic cancer contains several changes. T and N classification incorporate tumor size and number of positive lymph node (LN). The aim of this study was to evaluate the impact on the outcomes of the new classification for the patients who underwent curative resection and received adjuvant treatment with S-1. Methods: We retrospectively reviewed 96 patients who underwent curative resection for pancreatic ductal adenocarcinoma and received adjuvant treatment with S-1 (40, 50, or 60 mg according to body-surface area, orally administered twice a day for 28 days followed by a 14-day rest, every 6 weeks [one cycle], for up to four cycles) at our institution between January 2007 and December 2015. Inclusion criteria were as follows: PS0/1, adequate-organ functions, no critical complication, start of adjuvant therapy within 10 weeks after resection, and no active concomitant malignancy. Results: 66 patients were satisfied with these criteria. Patients characteristics were as follows: median age 67 years (range, 43-83), male 40 (61%), Pancreatoduodenectomy / Distal / Total pancreatectomy 50/14/2, combined portal vein or superior mesenteric vein resection 25 (38%), no postoperative complication 25 (38%), Well/Moderately/Poorly differentiated type 23/41/2, the median tumor size 30mm (range, 13-130), the median number of dissected LN 25 (range, 10-60), the median number of positive LN 2 (range, 0-8), and the resection margin status (R0/1) 62/4. The distribution in the 8th edition (1A/1B/2A/2B/3) was 6(9%) / 10(15%) / 5(8%) / 36(54%) / 9(14%), respectively. 2-year overall survival (OS) and relapse-free survival (RFS) were 70% and 52%. In the 8th edition staging system (1A/1B/2A/2B/3), 2-year OS and RFS were 100/90/80/66/40% and 83/70/53/49/22%, respectively. 2-year OS and RFS by T classification according to AJCC 8th edition were 100/68/56% and 90/39/56% (T1/2/3), while those by N classification were 90/66/40% and 70/49/22% (N0/1/2), respectively. Conclusions: The survival was poor with progress of the stage in the new classification. Especially at N stage, it might be suggested an association with prognosis.
Variations in DNA repair genomic alterations and tumor mutation burden in biliary tract cancer (BTC) subtypes.
Authors: Abdel-Wahab Reham , Ali Siraj Mahamed , Borad Mitesh J. , Shroff Rachna T. , Kwong Lawrence , Vauthey Jean-Nicolas , Koay Eugene Jon , Zuo Mingxin , Rashid Asif , Schrock Alexa Betzig , Ross Jeffrey S. , Bekaii-Saab Tanios S. , Javle Milind M.
Published: January 2019

263

Background: DNA repair genomic alterations (GAs) have been identified in 12% of Intrahepatic cholangiocarcinoma (IHCCA), 26% of extrahepatic CCA (EHCCA) and 8% of gallbladder cancer (GBC) patients (pts) ( Cancer 2016;122:3838–3847). Recently, the Cancer Genome Atlas (TCGA) has described more than 20 mutated DNA repair genes, many of which were not previously represented in prior reports. DNA repair GAs including MSI are associated with higher tumor mutational burden (TMB). Our study aim is to identify variations in the frequency of DNA repair GAs in IHCCA, EHCCA, and GBC. Methods: Hybrid capture-based next-generation sequencing of 422 fixed formalin paraffin embedded (FFPE) tissue blocks of BTC including; 270 IHCCA, 60 EHCCA, and 92 GBC was performed. We included 20 DNA repair genes and classified them as "direct" DNA repair genes ( ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that induce genomic instability ( BAP1, CDK12, MLL3, TP53, BLM). We calculated TMB on 1.1 Mb of sequenced DNA in 205 tissue specimens [138 IHCCA, 23 EHCCA, and 44 GBC] and classified into three groups; high (TMB-H; ≥ 20 mut/Mb), intermediate (TMB-I; 6-19mut/Mb) and low (TMB-L; < 6mut/Mb). Results: A distinct pattern of DNA repair GAs in each tumor type was detected. (Table 1). DNA repair GAs were more commonly noted in both EHCCA and GB (63%) as compared with IHCAA (45.2%) (p= .002). Direct DNA repair GAs were highest within EHCCA (25%), while indirect DNA GAs were predominant in GBC (59.8%) (p= 0.04 and 0.001, respectively). The frequency of TMB-H and TMB-I differed significantly between BTC subtypes. Pts with EHCCA and GBC had significantly higher TMB-H and TMB-I versus IHCCA. Conclusions: The frequency of DNA repair GA’s is higher in EHCCA and GBC as compared with IHCCA. These results may have implications for clinical trials with DNA repair inhibitors and immune checkpoint blockers. [Table: see text]
First prospective study evaluating effect of metformin (M) on disease control (DC) and activation of AMP-activated protein kinase (AMPKα) in patients (pts) with GI malignancies.
Authors: Godara Amandeep , Siddiqui Nauman S , Hachem Hilal , Martell Robert E. , Saif Wasif M.
Published: January 2019

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Background: Observational studies have demonstrated association of M with reduced cancer incidence and mortality in multiple cancer types, including GI. Anti-neoplastic effects of M are believed through many mechanisms including activation of AMP-activated protein kinase, which controls mammalian target of rapamycin (mTOR) growth regulatory pathway. Methods: In a pilot, delayed-start randomized study, non-diabetic pts with GI cancers were randomized to 2 arms, Stage 1: concurrent M (500mg twice daily) plus chemotherapy (M+C) vs. Chemo alone (C) followed by cross over to M+C arm in Stage 2, while adverse events (DLT) were assessed by CTCAE v.3.0. As a translational correlate, we used phosphorylation of AMPKα at Thr172 to measure AMPK activation by western blot technique in PBMCs isolated from pts before and after receiving M. These levels were correlated with radiological (RECIST 1.1) and tumor marker outcomes by descriptive analysis. Results: 41 pts with GI cancers (CRC: 22, PC: 12, GE: 4, BD: 2, others: 1) were treated in this trial. Mean duration of M therapy was 85 days (range: 9-443). There was no significant difference in grade 3 or above DLT in M+C vs. C arm (14% vs. 12% respectively). Gel band density analysis on 19 pts showed that 63% pts had increased phosphorylation of AMPKα after M (ratio of phospho-AMPKα after M to before M > 1) with mean = 1.227 (± 0.134). RECIST 1.1 restaging showed DC in 55% pts and 45% pts had decline in tumor markers. 8 of 12 pts with APC showed DC at the completion of study. Of note, 60% of pts with DC also showed increase in phosphorylation of AMKα. Conclusions: Our study is the first human study that prospectively demonstrates the impact of M on AMPKα phosphorylation, thus implying a potential role of M both as a chemopreventive and chemotherapeutic agent in GI cancers. Our study also shows the safety of M across various chemoregimens, providing a platform and justification for future studies. Potential benefits of M in preventive and treatment settings warrant further investigation in adequately powered prospective studies. We aim to perform a dose-escalation of M in our next study with additional metabolomics correlates. Clinical trial information: NCT01442870.
Prognostic value of serum interleukin-6 and YKL-40 and systemic inflammatory response in patients with unresectable pancreatic cancer.
Authors: Chen Inna , Dehlendorff Christian , Jensen Benny Vittrup , Pfeiffer Per , Bjerregaard Jon K. , Johansen Astrid Zedlitz , Nielsen Svend Erik , Andersen Fahimeh , Hollander Niels Henrik , Yilmaz Mette K. N. , Rasmussen Louise Skau , Johansen Julia S.
Published: January 2019

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Background: Interleukin-6 (IL-6) and YKL-40 (CHI3L1) are produced by pancreatic cancer (PC) cells and macrophages and activate inflammation. The aim of this prospective-retrospective biomarker study was to determine the prognostic value of serum IL-6 and YKL-40 and systemic inflammatory response in patients with PC receiving palliative chemotherapy. Methods: 625 patients with PC (M/F: 283/342; age <70 vs. ≥70: 395/230; ECOG PS of 0/1/2/3: 214/315/92/4; stage 3 vs. 4: 129/496; treated with gemcitabine n=437, FOLFIRINOX n=117, gemcitabine and nab-Paclitaxel n=54 or other n=17) were included in the BIOPAC biomarker study from 5 hospitals in Denmark. Pretreatment serum values of IL-6 (R&D Systems), YKL-40 (Quidel), and CA 19-9 (Siemens) were determined. Patients were grouped as low vs. high, dichotomized using cut-off for IL-6 > 4.92 pg/ml, for CA19-9 > 2183 U/ml and for YKL-40 > 95% age-corrected percentile. The main outcome was overall survival (OS) and hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were computed using Cox proportional hazards regression. Results: 598 (95.7%) patients died during follow-up. In univariate analysis elevated IL-6 (HR 1.93, 95% CI 1.63-2.28) and elevated YKL-40 (HR 1.74, 95% CI 1.47-2.05) were associated with short OS. Similar results were found if IL-6 and YKL-40 were included as continuous log2-transformed variables. Multivariable analysis showed that elevated IL-6 (HR 1.61, 95% CI 1.33-1.94), elevated YKL-40 (HR 1.36, 95% CI 1.13-1.64), elevated CA19-9 (HR 1.30, 95% CI 1.09-1.56), higher PS (1 vs. 0; HR 1.46, 95% CI 1.21-1.77 and PS 2 vs. 0; HR 2.73, 95% CI 2.08-3.58) and stage 4 vs. 3 (HR 1.79, 95% CI 1.44-2.24) were independently associated with a poor OS. In a subgroup of 386 patients with available laboratory data, higher C-reactive protein (HR 1.20, 95% CI 1.13-1.26), white blood cells (HR 1.41, 1.17-1.71) and absolute neutrophils count (HR 1.35, 95% CI 1.15-1.59) log2-transformed and adjusted for age, sex, PS, CA 19-9 and stage were associated with short OS. Conclusions: Serum IL-6, YKL-40 and CA19-9 along with CRP, WBC and ANC are independent prognostic biomarkers in patients with unresectable PC.
Expression of PD-L1 in periampullary adenocarcinoma: Relationship with morphological type, the immune microenvironment and prognosis.
Authors: Rastegar Nezhad Bahar Matilda , Heby Margareta , Lundgren Sebastian , Nodin Bjorn , Leandersson Karin , Elebro Jacob , Karnevi Emelie , Jirstrom Karin
Published: January 2019

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Background: Overall survival for patients with periampullary adenocarcinoma, including pancreatic cancer, continues to be poor. Pancreatic cancer is characterized by a largely immunosuppressive microenvironment, but blockade of the programmed death ligand 1 (PD-L1) pathway has still not been effective. Reports on the prognostic value of PD-L1 expression in pancreatic and in particular periampullary cancer are sparse. The aim of this study was therefore to analyze PD-L1 expression in periampullary adenocarcinoma, with specific reference to morphological type, tumor-infiltrating immune cells, and survival. Methods: PD-L1 expression in tumor cells (TC) and immune cells (IC) was assessed by immunohistochemistry on tissue microarrays with primary tumors from a retrospective consecutive cohort of 175 patients with resected periampullary adenocarcinoma, 65 of intestinal(I)-type and 110 of pancreatobiliary(PB)-type. Correlations with various immune cells were calculated with non-parametric tests. Cox proportional hazards models were applied to calculate hazard ratios (HR) and 95% confidence intervals (CI) for death. Results: TC PD-L1 expression was not associated with any clinicopathological factors nor with survival. IC PD-L1 ( > 10%) expression was higher in I-type than in PB-type tumors (p < 0.001), and correlated with defect mismatch repair (p = 0.012) and lymph node negativity (p = 0.016). IC PD-L1 was not prognostic in PB-type tumors. High IC PD-L1 was associated with a prolonged survival in the entire cohort (HR = 0.59, CI 0.40-0.88), and in I-type tumors (HR = 0.38, CI 0.18-0.81), but not after adjustment for other prognostic factors. In I-type tumors, high IC PD-L1 correlated with high density of T cells (CD3+, CD8+, FoxP3+), but not with B cell or macrophage density. There were no significant associations between IC PD-L1 expression and any other immune cells in PB-type tumors. Conclusions: High PD-L1 expression in IC is associated with a T cell dense tumor microenvironment and a prolonged survival in I-type, but not in PB-type, periampullary adenocarcinoma, thus indicating that the effect of immune-modulating therapies may differ by morphological type.
Mismatch repair deficiency in cholangiocarcinoma.
Authors: Kunk Paul Raymond , Obeid Joseph Mounir , Winters Kevin , Pramoonjago Patcharin , Brockstedt Dirk G. , Giobbie-Hurder Anita , Stelow Edward B , Bauer Todd W. , Slingluff Craig L. , Rahma Osama E.
Published: January 2019

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Background: Cholangiocarcinoma (CC) is a fatal malignancy with an unmet treatment need. With the approval of immunotherapy for solid tumors with mismatch repair (MMR) deficiency, there is a renewed interest in MMR testing. Little is known about the incidence of MMR deficiency in CC or its correlation to survival, immune cell infiltration, PD-L1 and other proteins expressed in CC such as mesothelin. Methods: CC tumors were identified from patients treated at the University of Virginia from 2000-2014. Tissue microarrays (TMAs) were constructed of 3-4 cores from each tumor and were stained by immunohistochemistry for MMR genes (MLH1, PMS2, MSH2, MSH6), mesothelin, PD-L1 and immune cells. TMAs were scanned using the Leica SCN400 and analyzed using the Digital Image Hub software. Stain intensity thresholds for defining positive cells were determined by two users and recorded as an average of all cores from each tumor. Mesothelin and PD-L1 expression were measured as a percentage of positive tumor cells. Correlation with overall survival was assessed using log-rank tests and classification and regression trees, with p values < 0.05 considered significant. Results: Ninety-one tumors were analyzed: 24 intrahepatic, 33 hilar, and 34 distal. MMR deficiency was found in 20 tumors (22%). None of the MMR deficient tumors co-expressed PD-L1 (>1%), which was found in 15% of the remaining tumors. T cell infiltration (CD4, CD8 and FoxP3) did not differ between MMR deficient or proficient tumors. Patients with MMR deficiency had a trend towards worse survival compared to those with proficiency (median OS: 19.2 vs. 28.1 months, p = 0.07). MMR deficient tumors showed a lower mesothelin expression compared to MMR proficient tumors, median 8 vs. 129 positive cells per TMA (p = 0.08). Patients with MMR deficiency and low mesothelin expression had a worse outcome compared to patients with MMR proficiency and high mesothelin expression (median OS: 14.5 vs. 30.0 months, p = 0.05). Conclusions: Given the high rate of MMR deficiency, all CC tumors should be tested and may benefit from anti-PD-1 therapy. The poor prognosis of MMR deficient CC may be independent of T-cell infiltration and additional studies are needed to better characterize the genetic and molecular landscape of this subset of tumors.
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

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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

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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

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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

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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

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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

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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.
Global Protein Aberration Score (GloPAS): A comprehensive risk score to predict hepatocellular carcinoma biology and estimate patients’ survival.
Authors: Kaseb Ahmed Omar , Zohner Emma , Xiao Lianchun , Wang Zeya , Hassan Manal , Abdel-Wahab Reham , Ballard Karri , Wolff Robert A. , Amin Hesham M. , Wang Wenyi , Yao James C. , Morris Jeffrey
Published: January 2019

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Background: Existing hepatocellular carcinoma (HCC) staging systems use a small number of empirically selected clinical/biological variables. We hypothesize that GloPAS (global protein aberration score) will capture a more global measurement of disease biology that can partition HCC into three subsets: (1) essentially normal profiles, (2) extremely aberrant profiles, and (3) slightly aberrant profiles. Methods: We collected plasma samples and clinical data prospectively from 767 HCC patients (pts) and 200 healthy controls, and quantified 317 pts using Myriad RBM CLIA-certified panel, Austin, TX. We applied a deconvolution algorithm, originally developed for determining percent normal contamination for tumor, to quantify the degree of global protein aberration for each pt relative to normal controls. We defined three distinct groups of pts with low ( < 0.3), medium (0.3-0.8), and high ( > 0.8) GloPAS and assessed GloPAS association with overall survival (OS) and other prognostic factors using log-rank tests and compared the prognostic abilities of GloPAS vs. existing systems using concordance index(C-index). We developed a single-sample GloPAS (ssGloPAS) using an algorithm that can be applied to single sample setting. Results: Although determined without using information about OS or any pt-level clinical or demographic factors (i.e. unsupervised), GloPAS showed remarkable prognostic separability (low/med/high GloPAS, with median OS 38.2mo/18.3mo/7.1mo, p < 0.0001). GloPAS prognostic ability was far above any existing HCC staging system (C-index = 0.75 vs. 0.58-0.70 p < 0.0001), demonstrating even more prognostic information than key factors as metastatic status and vascular invasion. The ssGloPAS was able to recapitulate the global signal captured by the GloPAS score with a much smaller subset of 14 proteins. Conclusions: GloPAS significantly improved prediction of OS and prognostic stratification of HCC. After further validation, ssGloPAS could be used to guide therapy decisions and stratify HCC pts in clinical trials. The novel concept underlying GloPAS methodology can be applied to other cancers to build disease-specific prognostic scores.
Somatic copy number profiling of hepatocellular carcinoma circulating tumor cells.
Authors: Court Colin MacDonald , Hou Shuang , Winograd Paul , Sadeghi Saeed , Finn Richard S. , Song Min , Kaldas Fady M , Busuttil Ronald W , Graeber Thomas , Tomlinson James S , Tseng Hsian-Rong , Agopian Vatche G
Published: January 2019

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Background: Copy number variations (CNVs) have shown prognostic and predictive utility in hepatocellular carcinoma (HCC) but their use from percutaneous biopsies is limited due to HCC’s significant tumor heterogeneity. We investigated the feasibility of obtaining CNV profiles from circulating tumor cells (CTCs) as a liquid biopsy for HCC. Methods: Using a microfluidic HCC-specific CTC assay, CTCs were isolated from 10 patients with HCC and low-resolution (~0.01x) whole genome sequencing performed to establish CNV profiles. Primary tumor, peritumoral liver, and germline DNA was sequenced for comparison. Results: Sequencing of 18 CTC samples (median 4 CTCs/sample) from 10 HCC patients using a low-resolution whole genome sequencing strategy (median 0.88 million reads/sample) revealed frequent copy number changes in previously reported HCC regions such as 8q amplifications and 17p deletions. Analysis of CNV profiles revealed that CTCs share a median of 80% concordance with the primary tumor and that CTCs clustered with their respective primary tumor for 9/10 samples. Sequencing of 7 different CTC samples from a single patient established the reproducibility of the assay. CTCs also demonstrated CNVs not seen in the primary tumor, some with prognostic implications. Conclusions: CNV profiling of HCC-CTCs is feasible and accurately recapitulates CNVs seen in the primary tumor. The use of CTC-derived genetic profiles as clinically relevant surrogates of HCC tumors demonstrates potential and should be explored further. [Table: see text]
Comprehensive genomic profiling to identify recurrent kinase fusions in pancreatic ductal adenocarcinoma.
Authors: Singhi Aatur D. , Greenbowe Joel R. , Chung Jon , Hendifar Andrew Eugene , Bahary Nathan , Schrock Alexa Betzig , Miller Vincent A. , Stephens Philip J. , Ross Jeffrey S. , Ali Siraj Mahamed , George Ben
Published: January 2019

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Background: Kinases activated by gene fusions represent an important class of oncogenes that have been detected in hematologic and solid malignancies. These fusion genes have been well-described in non-small cell lung cancer, and such patients often benefit from matched kinase inhibitors. Recent work in pancreatic ductal adenocarcinoma (PDAC) has also identified recurrent ALK and BRAF rearrangements. Further, patients harboring the former have benefited from ALK inhibitors, as previously reported. We present a survey of kinase fusion genes identified in a large, consecutive series of PDACs. Methods: In the context of clinical care, hybrid-capture based CGP was performed prospectively on 3,426 PDACs for up to 315 cancer-related genes and intronic regions of up to 28 genes that are commonly rearranged in cancer. Results: Overall, kinase fusion genes were identified in 32 (1%) patients with PDAC. The patients consisted of 8 females and 23 males, and ranged in age between 31 and 83 years (median, 58 years). PDACs harboring kinase fusions were predominantly KRAS-wildtype (97%). In fact, the prevalence of kinase fusion genes among KRAS-wildtype PDACs was 8%. Gene fusions involved BRAF (n = 22), ALK (n = 5), NTRK (n = 3) and MET (n = 2). Concurrent genomic alterations included CDKN2A/B (41%), TP53 (28%), GNAS (19%), SMAD4 (16%), MCL1 (16%), ARID1A (13%) and MYC (13%). Updated clinical history will be presented on patients, who previously benefitted from ALK inhibitors. Conclusions: Recurrent gene fusions involving BRAF, ALK, NTRK and MET occur in a subset of PDACs. Although rare, these kinase fusions potentially represent actionable targets and screening should be considered, especially in KRAS-wildtype PDACs.
Incidence and risk factor analysis of the postoperative delirium after gastrointestinal surgery: An exploratory analysis of a prospective, randomized phase II trial.
Authors: Amano Shinya , Aoyama Toru , Kamiya Mariko , Morita Junya , Maesawa Yukio , Sawazaki Sho , Numata Masakatsu , Sato Tsutomu , Oshima Takashi , Rino Yasushi , Yukawa Norio , Masuda Munetaka
Published: January 2019

30

Background: The postoperative complications, delirium are a particularly common morbidity after gastrointestinal surgery. Postoperative delirium makes patient management much more difficult, increases costs, and causes severe discomfort to the patient. The aim of this study was to evaluate the incidence of the postoperative delirium and a predictor for postoperative delirium using phase II clinical trial data. Methods: We analyzed the cases that were enrolled to randomized clinical trials of the efficacy and safety of TJ-54 (Yokukansan; a traditional Japanese medicine [Kampo]) for the prevention and/or treatment of postoperative delirium in a randomized phase II trial of patients receiving surgery for gastrointestinal and lung malignancies (UMIN000005423). The American Psychiatric Association’s the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) was used to assess. A uni- and multivariate logistic regression analyses was performed to identify risk factors for morbidity. Results: Between October 2009 and July 2011, a total of 186 patients were registered to the Yokukansan trial. Among them, 167 patients received surgery for gastrointestinal malignancy and were eligible for the present study. The incidence of postoperative delirium was 9.0% (15 patients) and postoperative delirium was the most common postoperative complication in the study. Risk factors for postoperative delirium were analyzed by uni- and multi-variate analyses using clinical factors determined before the enrollment of the study. Among these, high patients’ age ( > 80 years) and low MMSE score ( < 27) were identified as significant independent risk factor for postoperative delirium (Odds ratio: 3.90, 95% CI; 1.25-12.16, p = 0.013 and Odds ratio: 0.24, 95% CI; 0.08-0.73, p = 0.013). Conclusions: The major of the findings were that high patients’ age (≥ 80 years) and low MMSE score ( < 27) were significant independent risk factors for predicting postoperative delirium. Careful attention for postoperative delirium is required in patients with high patients’ age and MMSE score when surgeons perform surgery for gastrointestinal malignancies. Clinical trial information: 000005423.