bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gastric cancer liver metastasis: Optimal management for oligo-metastatic disease.
Authors: Ito Hiromichi , Takemura Nobuyuki , Ono Yoshihiro , Sato Takafumi , Mise Yoshihiro , Inoue Yosuke , Takahashi Yu , Saiura Akio 
Published: January 2019

136 Background: The role of surgery for gastric cancer liver metastasis (GCLM) has not been established and particularly, the optimal management for liver-isolated, oligo-GCLMs remains controversial. The aims of this study were to review the outcomes for our patients with GCLM who underwent liver resection and to define the optimal selection criteria for resection. Methods: The medical records of patients who underwent liver resection for GCLMs with curative intent at our institution from 1993 through 2018 were reviewed. Our criteria for liver resection included absence of extrahepatic disease, and the limited number of liver metastasis (often 3 or less). Results: Total 101 patients with GCLM (77 men [76%], median age 66 years) were included. Forty-seven patients (46%) had synchronous metastasis and all underwent simultaneous resection with the primary disease. Those with synchronous disease received neoadjuvant therapy more often than those with metachronous disease (63% vs 37%, p = 0.021). Median RFS and OS for the entire cohort were 11 months and 39 months, respectively, and 5-year-OS rate was 41%. Of note, 25 patients achieved survival longer than 5 years without any recurrence thereafter with median follow-up of 137 months. In the multivariate analyses, elevated CEA 50 ng/ml or greater and nodal status of the primary were associated with shorter RFS, while primary T4 disease, liver tumor 5cm or great and elevated CEA were associated with shorter OS (Table 1). Conclusions: For well selected patients with GCLM, liver resection is an effective therapy not only to prolong disease-free time, but also to achieve cure. CEA is useful to select patients with GCLM who unlikely benefit from aggressive surgery. [Table: see text]
Predictors of lymphopenia in esophageal cancer patients receiving photon or proton radiation therapy: A dosimetric analysis.
Authors: Routman David M. , Whitaker Thomas J , Day Courtney N. , Harmsen William S. , Neben-Wittich Michelle A. , Haddock Michael G. , Hallemeier Christopher Leigh , Merrell Kenneth 
Published: January 2019

147 Background: Lymphopenia during radiation therapy (RT) has been associated with worse oncologic outcomes in a number of malignancies, including esophageal cancer (EC). No studies to date have investigated specific dosimetric parameters associated with this lymphopenia in EC. We performed an analysis of RT dose to multiple organs at risk (OARs) to investigate associations with grade 4 lymphopenia (G4L). Methods: Consecutive EC patients receiving curative intent chemoradiotherapy +/- surgery between July of 2015 and December of 2017 were included. Lymphocyte nadir was defined as the lowest lymphocyte count during RT. G4L was defined as absolute lymphocyte count <200/mm3. Dose to OARs including aorta, body, bone marrow, heart, liver, lung, and spleen were calculated. Univariate logistic regression analyses were performed for each OAR at the 1, 5, 10, 15, 20, 30, 35, 40, and 50 Gy levels with volume receiving dose ‘x’(VxGy) analyzed as a continuous variable per 10% increase. Clinical tumor volume (CTV) and RT modality (photon vs. proton) as well clinical factors including sex, stage (I/II vs. III/IV), age (per 10 year increase), and BMI (per 5 unit increase) were also analyzed. Results: One hundred forty-four pts were identified for inclusion. Seventy-nine pts received photon RT and 65 proton RT. Chemotherapy was weekly carbotaxol (99%). G4L at nadir was 40% overall (56% photon, 22% proton). By organ, body V1-V30Gy (OR 1.45-8.18, p<0.01), heart V1-V30Gy (OR 1.24-1.49, p<0.01), liver V1-V35Gy (OR 1.23-2.75, p<0.01), lung V1-V30Gy (OR 1.26-5.73 p<0.01), and spleen V1-V40Gy (OR 1.26-1.49 p<0.01) were highly associated with G4L whereas dose to aorta and bone marrow were not. Advanced stage (OR, 3.92 p<0.01), photon vs. proton (OR 4.58 p<0.01), and CTV (per 100 cc’s (OR=1.21, p<0.01)) were also associated with G4L. Sex, age, and BMI were not associated with G4L. Conclusions: Low to intermediate dose volumes to OARs including body, spleen, liver, lungs, and heart were associated with G4L. These findings provide rational for the differences seen in rates of G4L for photon versus proton RT.
Outcomes in pancreatic adenocarcinoma (PDA) patients (pts) with genetic alterations in DNA damage repair (DDR) pathways: Results from the Know Your Tumor (KYT) program.
Authors: Pishvaian Michael J. , Blais Edik Matthew , Brody Jonathan Robert , Sohal Davendra , Hendifar Andrew Eugene , Chung Vincent , Mikhail Sameh , Rahib Lola , Lyons Emily , Tibbetts Lisa , Madhavan Subha , Matrisian Lynn McCormick , Petricoin Emanuel 
Published: January 2019

191 Background: Up to 17% of PDAs harbor mutations in the DDR pathway. However, the purely prognostic relevance of these mutations is unclear. Furthermore, outcomes in response to platinum-based therapies in PDA pts harboring mutations in a broad range of DDR genes, particularly beyond BRCA1/2 and PALB2, remain unexplored. Methods: We evaluated PDA pts enrolled in the KYT registry for whom we collected cancer related exome sequencing and clinical outcomes. Pts were categorized as resected and advanced (LAPC and metastatic pts), and tumor genomic profiles were categorized as DDR mutated (DDRmut) based on the presence of pathogenic alterations in BRCA1/2, PALB2 (Group 1), ATM, ATR, ATRX (Group 2), or BAP1, BARD1, BRIP1, CHEK1/2, RAD50/51/51B, or FANCA/C/D2/E/F/G/L (Group 3). Tumors harboring no DDR mutations were labelled DDR proficient (pDDR). Median overall survival (OS) was measured from the date of diagnosis until death. Results: The OS was similar in all resected pts, irrespective of exposure to platinum therapy (see Table). However, for the pts with advanced disease, OS was significantly longer for DDRmut vs. pDDR pts, particularly in the platinum-treated group; but no such difference was identified in the platinum-naïve pts. Detailed outcomes for the 3 Groups will be presented, but in general the OS in pts with mutations in all 3 DDRmut Groups was greater than for the pDDR pts; but again this difference was lost in the platinum-naïve pts. Conclusions: Advanced DDRmut pts have an improved OS when treated with platinums, compared to pDDR pts. But, in the absence of platinum-based therapy, there is no OS difference observed in DDRmut vs. pDDR pts, suggesting that DDR status has no pure prognostic value. These findings support the need to test all pts with advanced PDA, to ensure that DDRmut pts are treated with platinum-based therapy. [Table: see text]
Immune checkpoint inhibition (ICI) in combination with SBRT in patients with advanced pancreatic adenocarcinoma (aPDAC).
Authors: Brar Gagandeep , Xie Changqing , Floudas Charalampos S. , Morelli M. Pia , Fioravanti Suzanne , Walker Melissa , Mabry-Hrones Donna , Jones Jennifer C , Greten Tim F. 
Published: January 2019

192 Background: Chemotherapy in aPDAC has resulted in only modest improvements in outcome. The effectiveness of ICI monotherapy is also limited in PDAC, suggesting an immunogenic inert tumor microenvironment. SBRT is safe and effective in locally advanced PDAC and exhibits enhanced antitumor immunity. We hypothesize that ICI plus SBRT will improves immunomodulatory effects of ICI in patients with aPDAC resulting in a greater clinical benefit. Methods: Eligible patients with aPDAC were enrolled to four different treatment cohorts. Cohort 1: Durvalumab (Durva) 1500 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 2: SBRT 5 fractions x 5Gy followed by Durva. Cohort 3: Durva + Tremelimumab (Treme) 75 mg every 4 weeks + SBRT 1 fraction x 8Gy on day 1. Cohort 4: SBRT 5 fractions x 5Gy followed by Durva + Treme. This was continued until unacceptable toxicity or progression of disease. A biopsy was performed at baseline and pre-cycle 2 of treatment for exploratory correlative analysis. The primary objective was to evaluate the safety and feasibility of combining ICI and SBRT to enhance the efficacy of ICI. Results: 51 patients with aPDAC were enrolled and 31 patients were evaluable for the efficacy. The most commonly TRAEs were lymphopenia. Grade 3-4 AEs were lymphopenia and anemia. No dose limiting toxicities were seen. Out of total 31 evaluable patients, 1 patient achieved a confirmed partial response seen in Cohort 1 and 2 patients in Cohort 4, and 7 stable disease across the 4 treatment arms. Median PFS and OS was 1.7 months (95% CI 0.7-2.8 months) and 3.4 months (95% CI 0.9-11.4 months) in cohort 1; 2.6 months (95% CI 2.1-4.7 months) and 9.1 months (95% CI 3.4-18.7 months)in cohort 2; 1.6 months (95% CI 0.5-4.0 months) and 3.0 months (95% CI 0.7-6.6 months) in cohort 3; and 3.2 months (95% CI 1.5-16.5months) and 6.4 months (95% CI 1.5-17.6 months) in cohort 4. Conclusions: The combination of ICI and SBRT is safe and well tolerated in patients with aPDAC. The overall response rate of 9.6% including 2 patients who achieved a durable partial response lasting over 12 months, suggests meaningful clinical activity. This signifies that ICI and SBRT is a potential new treatment for aPDAC. Clinical trial information: NCT02311361.
Quality-adjusted life years assessment using cabozantinib for patients with advanced hepatocellular carcinoma (aHCC) in the CELESTIAL trial.
Authors: Abou-Alfa Ghassan K. , Mollon Patrick , Meyer Tim , Cheng Ann-Lii , El-Khoueiry Anthony B. , Kelley Robin Kate , Baron Ari David , Benzaghou Fawzi , Valcheva Velichka Valerieva , Hazra Saswati , Mangeshkar Milan , Freemantle Nicholas 
Published: January 2019

207 Background: In patients previously treated for aHCC, cabozantinib (cabo) led to longer overall survival and progression-free survival vs placebo (pbo) in the randomized, phase 3 CELESTIAL trial (NCT01908426; N = 707). CELESTIAL was stopped early for benefit at the second interim analysis. This post hoc analysis estimated the incremental quality-adjusted life years (QALYs) accrued in CELESTIAL. Methods: Health utility was elicited at each study visit using the EQ-5D-5L quality of life questionnaire. (completed by 82–100% of patients overall). UK crosswalk tariffs were applied for health states. Cumulative QALYs by patient were calculated by linear interpolation; for patients who were censored (31% of patients; including 9% within 100 days of randomization), the last observed utility value was carried forward to study end. The difference in restricted mean QALYs was calculated using generalized linear models, accounting for baseline utility, and with 0.06–0.08 QALYs considered the minimal important difference. Results: At day 50 after randomization (acute treatment phase), cabo was associated with a small reduction in mean total QALYs vs pbo (difference −0.003; 95% CI −0.005 to −0.002; p ≤ 0.001; n = 601 [cabo, n = 389; pbo, n = 212]). At day 100, there was a numerical benefit in mean total QALYs for cabo (difference +0.007; 95% CI −0.001 to 0.015; p = 0.103; n = 627 [cabo, n = 410; pbo, n = 217]), and at day 150 the difference was +0.032 QALYs (95% CI 0.017 to 0.047; p ≤ 0.001; n = 629 [cabo, n = 412; pbo, n = 217]) in favor of cabo. Over the entire follow-up, patients randomized to cabo accrued a mean of +0.092 (95% CI 0.016 to 0.169; p = 0.018; n = 700 [cabo, n = 465; pbo, n = 235]) additional QALYs compared with those receiving pbo. Using alternative Devlin weights for health states, the mean accrued QALYs with cabo was +0.115 vs pbo (95% CI 0.032 to 0.198; p = 0.007). Conclusions: Cabo was associated with an initial, small reduction in health utility. However, with continued treatment, health utility increased and at the end of the study there was a clinically and statistically significant benefit in mean QALYs in favor of cabo. Clinical trial information: NCT01908426.
Prevalence and molecular etiology of mismatch repair deficiency among gastrointestinal cancers.
Authors: Shukla Navika , Abrha Aser , Longacre Teri A. , Koff Rachel , Ford James M. , Fisher George A. , Haraldsdottir Sigurdis 
Published: January 2019

215 Background: In light of recent FDA approval of anti-PD-1 therapy for microsatellite unstable (MSI-H) or mismatch repair deficient (dMMR) solid tumors, identifying patients with dMMR tumors has become increasingly important. While screening for dMMR and MSI-H in colorectal cancer (CRC) is recommended, this screening is less commonly done for extracolonic gastrointestinal (GI) tumors. At Stanford Comprehensive Cancer Institute (SCCI), all GI cancer patients have been universally screened for dMMR via immunohistochemistry since January 2016. Methods: In this study, we undertook a retrospective review of all GI cancer patients screened for dMMR between January 2016 to December 2017. Data on patient characteristics, germline and tumor sequencing, and tumor characteristics were collected and reported. Results: A total of 1543 GI malignancies were screened for dMMR at SCCI during the study period. Colorectal (n = 711), pancreatic (n = 264), gastric (n = 159), and gastro-esophageal (n = 137) cancer were amongst the most frequently screened tumors. dMMR was detected in 7.1% of all GI malignancies. We detected the highest prevalence of dMMR in colorectal (69/711, 9.7%), followed by gastric (15/159, 9.4%), pancreatic (18/264, 6.8%), and gastro-esophageal cancer (6/137, 4.4%). Lynch syndrome was the most common etiology for dMMR in CRC patients (39.4%), double somatic (confirmed or possibly) mutations were most common in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation was the most common etiology in gastric (73.3%) and gastro-esophageal cancer (100%). Conclusions: Given the relatively high incidence of dMMR in GI malignancies, we strongly recommend screening all GI malignancies. Of note, we found higher than previously reported rates of dMMR within pancreatic cancer. Our results also suggest that while rare, double somatic mismatch repair mutations may be a significant pathway causing dMMR in pancreatic cancer.
Plasma GH as a diagnostic and prognostic biomarker in HCC without cirrhosis.
Authors: Carmagnani Pestana Roberto , Hassan Manal , Abdel-Wahab Reham , Abugabal Yehia I. , Girard Lauren , Hatia Rikita , Nguyen Van , Raghav Kanwal Pratap Singh , Morris Jeffrey , Rashid Asif , Wolff Robert A. , Amin Hesham M. , Kaseb Ahmed Omar 
Published: January 2019

227 Background: The association between the GH/IGF-1 axis and HCC was reported in patients (pt) with underlying cirrhosis. However, there is limited information among HCC pt without (w/o) cirrhosis. We herein investigated the role of GH as a circulating biomarker for HCC diagnosis and prognosis in pt w/o cirrhosis. Methods: Under IRB approval, we prospectively enrolled 1267 newly-diagnosed HCC pt in a case control study at the MD Anderson Cancer Center (2000-2015). Controls were healthy individuals (n = 1104). Plasma GH and AFP were measured 274 HCC pt w/o cirrhosis 200 healthy controls. IGF-1 was measured in 133 and 82 pt, respectively. We classified HCC pt into higher and lower GH values (cutoff for women, 3.7 µg/L; men, > 0.9 µg/L). Results: Most pt (74%) were male, with advanced BCLC staging (C-D, 74%) and 61% were older than 60y. Baseline GH was higher in HCC w/o cirrhosis (mean 3.3 µg/L) than controls (mean 0.4 µg/) (p < .001). ROC curve was plotted to assess diagnostic role. The AUC for AFP was 82.9 (p < .001); for GH 78.2 (p < .001). When only non-cirrhotic HCC pt with early stage (CLIP 0-2) and AFP < 20 ng/m were compared to controls, the GH/IGF-1 ratio had high prediction of early stage HCC - AUC 83 (95% CI 78-89%) (p < .0001). At a specificity of 90%, sensitivity of GH/IGF ratio was 67%. In addition, among HCC w/o cirrhosis, higher GH levels correlated with presence of vascular invasion (p < .001) and thrombosis (p = .004), tumor involvement of > 50% liver (p = .003), and more advanced BCLC (p < .001) and TNM staging (p < .001). Median overall survival (months) of HCC pt w/o cirrhosis with high GH levels was 13.1 (10.8-15.4) compared to 37.4 (19.8-55.1) of pt with lower plasma GH (p < .001). Multivariate cox-regression analysis identified high GH as an independent risk factor for mortality (HR = 1.8; 95% CI, 1.3-2.4; p < .001). Conclusions: Our study demonstrates the diagnostic and prognostic role of plasma GH in non-cirrhotic HCC and identifies the GH/IGF-1 ratio as a promising diagnostic marker for early stage HCC w/o cirrhosis and low AFP; this analysis excludes the confounding effect hepatocyte impaired function by presence of cirrhosis. Further studies are warranted to assess the causes of the observed differences.
Landscape of germline mutations in hepatobiliary carcinoma: Unrealized risk, untapped clinical trial opportunities.
Authors: Samadder Jewel , Rupp Margaret , Yang Shan , Michalski Scott T. , Lincoln Stephen E , Nussbaum Robert L. , Borad Mitesh J. , Esplin Edward D. 
Published: January 2019

236 Background: Hepatobiliary cancer (HBC), including cholangiocarcinoma, affects over 40,000 people in the U.S. each year, and results in over 30,000 cancer deaths annually. Despite continuing advances in next-generation sequencing (NGS), the understanding of germline genetic risk as it relates to these malignancies remains limited, and guidelines for the germline testing of these patients are lacking. We report the spectrum of pathogenic/likely pathogenic (P/LP) germline genetic variants observed in patients with HBC, and the clinical utility related to germline genetic test results. Methods: We retrospectively studied a consecutive series of 267 patients referred to Invitae for germline genetic testing based on a personal history of HBC, per an IRB approved protocol. Patients were evaluated with a multigene panel of up to 135 genes chosen by the ordering providers. De-identified clinical and family history information were reviewed as provided by clinicians. Results: Among 267 HBC patients 15% (n = 41) had P/LP variants identified in genes including MUTYH, ATM, CHEK2, BAP1, BRCA1, MLH1, BRCA2, PALB2, TP53, APC, CDH1, MSH6, and PMS2 (12% excluding MUTYH heterozygotes). Amongst patients with a family history (FH) of HBC, P/LP rate was 13%; for patients with a FH of cancers other than HBC, P/LP rate was 16%; for patients with no reported FH, P/LP rate was 13%. Conclusions: In this study, 15% of HBC patients had P/LP variants in cancer-risk genes. The clinical utility of these germline P/LP variants includes 32% of patients who were eligible for ongoing clinical treatment trials based on their germline test results (NCT02286687), 60% with clinical management recommendations per current NCCN guidelines, and cascade testing of at risk family members. These data justify comprehensive germline multigene panel testing in all HBC patients, in view of the potential impact on clinical management for a substantial fraction of positive patients as well as facilitating cascade testing for risk assessment of family members.
A phase Ib dose escalation study of vantictumab (VAN) in combination with nab-paclitaxel (Nab-P) and gemcitabine (G) in patients with previously untreated stage IV pancreatic cancer.
Authors: Davis S. Lindsey , Cardin Dana Backlund , Shahda Safi , Lenz Heinz-Josef , Dotan Efrat , O'Neil Bert , Kapoun Ann M. , Stagg Robert J. , Berlin Jordan , Messersmith Wells A. , Cohen Steven J. 
Published: January 2019

249 Background: Vantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. A phase Ib study of VAN in combination with Nab-P and G was performed in patients with untreated stage IV pancreatic adenocarcinoma. Methods: Patients received VAN at escalating doses (3-7 mg/kg) in combination with standard dosing of Nab-P and G according to a 3+3 design. Due to fragility fractures occurring in this and other related clinical trials, dosing on an every 2 week schedule in cohorts 1 and 2 was transitioned to every 4 week dosing for cohorts 3 through 5. In these later cohorts, a minimum of six patients were treated at each dose level and additional criteria for maximum tolerated dose (MTD) integrating bone safety parameters were added. The bone safety plan was also revised for these cohorts. Sequential dosing of VAN followed by Nab-P and G was explored in cohort 5. Results: Thirty-one patients (52% male, 48% female) were enrolled and treated in 5 dosing cohorts. Median age was 66. Most common study-treatment related adverse events were nausea (68%) and fatigue (52%). One dose limiting toxicity (DLT) event occurred in the study population—grade 3 dehydration in 1 of 9 patients in cohort 4 (5 mg/kg q4w). Fragility fractures attributed to VAN occurred in two patients in cohort 2 (7 mg/kg q2w). Once the dosing schedule was revised to every 4 weeks, the maximum administered VAN dose was 5 mg/kg. No fragility fractures attributed to VAN occurred in these cohorts; pathologic fracture not attributed to VAN was documented in 2 patients. The study was terminated due to lack of an acceptable therapeutic index. Partial response was documented in 13 patients (42%) and stable disease in 11 (36%). Conclusions: The MTD of VAN plus Nab-P and G was not determined, but the maximum administered dose (MAD) of VAN, 7 mg/kg every 2 weeks, was considered unsafe related to bone toxicity, a known effect of WNT inhibition. After the study was revised, the MAD was 5 mg/kg every 4 weeks, with no protocol-specified bone toxicity observed (n = 16). Clinical trial information: NCT02005315.
Comprehensive genomic analysis of metastatic pancreatic ductal adenocarcinoma (mPDAC) reveals a significant proportion of clinical actionable aberrations.
Authors: Lee Michael , Jones Martin R , Williamson Laura , Topham James Thomas , Addison Sean , Wong Hui-Li , Denroche Rob , Jang Gun Ho , Karasinska Joanna , McGhie John Paul , Gill Sharlene , Lim Howard John , Yip Stephen , Knox Jennifer J. , Gallinger Steven , Laskin Janessa J. , Marra Marco A. , Jones Steven J. M. , Sschaeffer David F , Renouf Daniel John ,   POG PDAC
Published: January 2019

273 Background: Substantial progress has been made in the understanding of the genomic landscape of PDAC, but the clinical utility of these data remains uncertain. Methods: As part of the BC Cancer Personalized Oncogenomics (POG) and PanGen studies, whole genome analysis and transcriptome sequencing were performed on fresh biopsy and blood sample from 47 mPDAC patients. Genomic findings informed therapy choices including potential eligibility for the CCTG PM.1 molecular basket trial. Results: Cohort consists of 53% male, average age 57.8, 34/47 had ≥2 lines of treatment. 37/47 biopsies were from liver and 26/47 were collected pre-treatment. 8/47 (17%) patients had aberrations with strong evidence of clinical actionability. These include 2 germline BRCA2, 1 germline BRCA1, 1 somatic XRCC2 homozygous deletion with strong COSMIC signature 3, all predictive of platinum sensitivity. Patients with XRCC2 deletion and BRCA1 had over 2 years on FOLFIRINOX. Fusions affecting the NRG1 gene were identified in 3 patients, all with KRAS wildtype tumours, which may confer ERRB inhibitor sensitivity. 1/3 NRG1 fusion patients had thus far been treated with the ERBB inhibitor afatinib, with reduction of CA19-9 from >120,000 to 7246 and dramatic response noted on PET CT imaging one month post treatment. One patient had mismatch repair deficiency, and a high mutational burden, suggestive of immune checkpoint inhibitor sensitivity. In total 85% (40/47) sequenced mPDAC patients had potentially actionable mutations which includes CCTG PM.1 trial eligibility: 24/47 with cell cycle dysregulation (CDK4/6 inhibitor arm), 4/47 with high homologous recombination defects (PARP inhibitor arm), 1/47 ERBB2 amplification (anti-HER2 arm), 2/47 high expression of FGFR1 (Sunitinib arm) and 1/47 with high FLT4 and IGF1R expression (Axitinib arm). Conclusions: More routine use of comprehensive genomic analysis should be considered in mPDAC given finding of high degree of actionability. Importantly, a significant proportion (17%) had findings with strong evidence of clinical impact.(NCT02155621, NCT02869802, NCT03297606)