bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of change in AFP > 15 ng/ml/month with stage at diagnosis and mortality in patients with hepatocellular carcinoma (HCC).
Authors: Ilagan-Ying Ysabel , Kaplan David Edward , Taddei Tamar H. , Njei Basile 
Published: March 2017

255 Background: In a recent study, a change in AFP > 15 ng/ml/month was associated with poor post-transplant HCC survival. We hypothesized that change in AFP is associated with stage of HCC at diagnosis and mortality. Methods: Patients with potential HCC from 2008-2010 were identified by querying the Veterans Administration Corporate Data Warehouse. Diagnostic confirmation and tumor staging was obtained by manual chart abstraction. Dates of death were ascertained and censored from 12/31/2014. Logistic regression analysis was performed to determine the association between change in AFP and stage at diagnosis. Multivariable cox regression analysis adjusting for severity of liver disease was performed to determine the association between change in AFP and all-cause mortality. Results: Of 3,988 HCC cases, change in AFP > 15 ng/ml/month was associated with presentation at BCLC stage B (OR 2.26, CI 1.54-3.33, p < 0.001) and C (OR 3.39, CI 2.25-5.01, p < 0.001). There was no statistically significant association between AFP > 15 ng/ml/month with stage BCLC 0 or A (early HCC), or with BCLC stage D, likely reflecting a greater burden of liver disease severity over tumor burden in Stage D. Change in AFP > 15 ng/ml/month was associated with increased all-cause mortality (HR 1.49, CI 1.37-1.62, p < 0.001). Conclusions: In a large cohort of US Veterans with HCC, change in AFP > 15 ng/ml/month may be a useful prognostic marker for presentation with advanced stage cancer and all-cause mortality.
A novel t-stage classification system for adrenocortical carcinoma: Proposal from the U.S. Adrenocortical Carcinoma Study Group.
Authors: Poorman Caroline Elizabeth , Ethun Cecilia Grace , Postlewait Lauren McLendon , Tran Thuy , Pawlik Timothy M. , Wang Tracy S , Hatzaras Ioannis , Phay John E , Fields Ryan C , Weber Sharon M. , Sicklick Jason K. , Yopp Adam Charles , Prescott Jason David , Duh Quan-Yang , Solorzano Carmen C. , Votanopoulos Konstantinos Ioannis , Poultsides George A. , Maithel Shishir Kumar 
Published: March 2017

266 Background: The 7th AJCC T-stage classification system for adrenocortical carcinoma (ACC), based on size and extra-adrenal invasion, does not adequately stratify patients by survival. Lymphovascular invasion (LVI) is a known poor prognostic factor. We propose a novel T-stage system that incorporates LVI to better risk-stratify patients undergoing resection for ACC. Methods: Patients undergoing curative-intent resections for ACC from 1993-2014 at 13 institutions comprising the US ACC Study Group were included. Primary outcome was disease-specific survival (DSS). Results: Of 265 patients with ACC, 149 had complete data for analysis. The current T-stage system failed to differentiate patients with T2 vs T3 disease ( p= 0.10). Presence of LVI was associated with worse DSS compared to no LVI (36 vs. 168mos; p= 0.001). After accounting for the individual components of the current T-stage system (size and extra-adrenal invasion), LVI persisted as a poor prognostic factor on multivariable analysis (HR 2.14, 95% CI 1.05-4.38, p= 0.04). LVI positivity further stratified patients with T2 and T3 disease, (T2: 37mos vs median not reached; T3: 36 vs 96mos; p =0.03), but did not influence survival in patients with T1 or T4 disease. By incorporating LVI, a new T-stage classification system was created: [T1: < 5cm, (-)local invasion, (+/-)LVI; T2: > 5cm, (-)local invasion, (-)LVI OR any size, (+)local invasion, (-)LVI; T3: > 5cm, (-)local invasion, (+)LVI OR any size, (+)local invasion, (+)LVI; T4: any size, (+)adjacent organ invasion, (+/-)LVI]. Each progressive new T-stage group was associated with worse median DSS (T1: 167mos; T2: 96mos; T3: 37mos; T4: 15mos; p< 0.001). Conclusions: The current AJCC T-stage system for ACC does not adequately stratify patients by survival, particularly for T2 and T3 disease. The proposed T-stage classification system, which incorporates lymphovascular invasion, better differentiates T2 and T3 disease and accurately stratifies patients by disease-specific survival. If externally validated, this novel T-stage classification should be considered for future AJCC staging systems.
Loss of HER2 positivity after anti-HER2 chemotherapy in HER2-positive gastric cancer patients: Results of GASTric cancer HER2 reassessment study 3 (GASTHER3).
Authors: Seo Seyoung , Ryu Min-Hee , Ahn Ji Yong , Park Yangsoon , Park Sook Ryun , Ryoo Baek-Yeol , Park Young Soo , Lee Gin Hyug , Jung Hwoon-Yong , Kang Yoon-Koo 
Published: March 2017

27 Background: Although discordance of HER2 positivity between primary and metastatic lesions was well known, changes of HER2 positivity after chemotherapy have not been studied in gastric cancer (GC). Methods: A total of 48 HER2-positive advanced GC (AGC) patients who were treated with trastuzumab-containing 1stline chemotherapy and had paired biopsies at baseline and after progression were enrolled. Scores of HER2 immunohistochemistry (IHC) were reviewed and in situ hybridization (ISH) was conducted when tissues were available. Results: Thirty-nine patients were treated with capecitabine, cisplatin/oxaliplatin, and trastuzumab (XPT) while the other 9 received XPT plus pertuzumab/placebo. Objective response rate (ORR) was 76% (26 out of 34) and median progression free survival (PFS) and overall survival were 8.3 and 16.3 months, respectively. At baseline, HER2 was positive with IHC 2+ and ISH+ in 5 and with IHC 3+ in 43. Loss of HER2 positivity after progression was observed in 14 (28.6%); 10 with IHC 0 or 1+ and 4 with IHC 2+ but ISH- at 2nd biopsy. HER2 remained positive in the other 34; 4 with IHC2+ and ISH+, and 30 with IHC 3+ at 2nd biopsy. Applying H-score formula, mean scores decreased from 201 to 170 (Wilcoxon test; p=0.047). HER2 genetic heterogeneity (5% to <50% of tumor nuclei showing a HER2:CEP17 ratio ≥2) was noted only 1 out of 34 ISH-assessable patients (2.9%) at baseline while 7 out of 32 ISH-assessable patients (21.9%) had heterogeneity at 2nd biopsy. The mean ratio was changed from 6.5 (1.2-15.8) to 5.0 (0.4-15.2) (paired t-test, p=0.019) and all patients with genetic heterogeneity at 2ndbiopsy showed HER2 negative conversion. Among 13 who received 2ndline T-DM1, 3 showed HER2 negative conversion. Those 3 had no objective response at all and very short PFS (1.2, 1.3 and 3.4 months), whereas the others with stable HER2 status showed 44% of ORR and median PFS of 2.7 (0.4-36.8) months. Conclusions: A substantial portion of initially HER2-positive AGC patients showed HER2 negative conversion with increased HER2 heterogeneity after trastuzumab-containing chemotherapy. Loss of HER2 positivity could be a predicting factor for 2nd line anti-HER2 treatment.
Retrospective study of CT-guided radiofrequency ablation and laparoscopic radiofrequency ablation in the treatment of recurrent small hepatocellular carcinoma against the diaphragmatic dome.
Authors: Zheng Qin , Ding Huaiyin , Zhu Chuandong , Wang Lixue , Wan Yuan 
Published: March 2017

272 Background: Radiofrequency ablation (RFA) have been used to treat hepatocellular carcinoma (HCC) in the subphrenic area. Very few studies focus on ablation of recurrent small HCC against the diaphragmatic dome. The therapeutic safety, efficacy, and hospital fee have never been compared between CT guided RFA and laparoscopic RFA (L-RFA) either. Methods: CT guided RFA and L-RFA were performed in totally 116 patients with 151 local recurrent HCC lesions abutting the diaphragm. We compared major and minor postoperative complications, hospital stay and fee, overall survival (OS), and local tumor progression (LTP) between two groups for evaluating respective therapeutic efficacy and safety. Moreover, in CT-guided percutaneous RFA group, depending on the locations of recurrent HCC nodules differentiated puncture paths and ablation methods were used, and intraoperative complications were recorded. Results: There is no significant difference in OS and LTP between CT- guided RFA and LRFA.In recorded postoperative complications, the morbidity in CT-guided RFA group is lower than that of L-RFA group. The average safety margin is 8 and 11 mm in CT-guided RFA and LRFA group, respectively. The shoulder and back pain is significantly high in L-RFA group probably due to pneumoperitoneum. Moreover, overall hospital stay and cost is also lower in CT-guided RFA group. Conclusions: Both CT-guided RFA and L-RFA are considered to be an effective approach for recurrent small HCC abutting diaphragm. Particularly, CT-guided RFA is an easy and economic with less complications if suitable puncture paths and ablation methods can be applied.
Effect of a mixed type Lauren's classification on agressiveness and lymph node metastasis in early gastric cancer.
Authors: Pyo Jeunghui , Lee Hyuk , Shin In Seub , Kim Tae Jun , Min Yang Won , Lee Jun Haeng , Kim Jae J. , Min Byung-Hoon 
Published: March 2017

28 Background: The clinicopathological features of mixed type (MT) early gastric cancer (EGC) according to Lauren’s classification remain uninvestigated. This study aimed to clarify the clinicopathological features of MT EGC, particularly in relation to lymph node metastasis (LNM) and long-term survival. Methods: This study included 5,309 patients who underwent gastrectomy for EGC. The clinicopathological features, LNM, and long-term outcomes of patients with MT carcinomas were compared to those with intestinal type (IT) and diffuse type (DT) cancers. Furthermore, we evaluated the predictors of LNM in each Lauren classification subgroup. Results: Patients with MT carcinomas were more likely to have larger tumors, submucosal invasion, lymphovascular invasion (LVI), and LNM compared to those with IT or DT carcinomas. Multivariate logistic regression analysis revealed that Lauren’s classification was a significant predictor of LNM ( P < 0.001). The significant predictors of LNM in MT carcinomas were female sex, greater tumor size, presence of submucosal invasion, and LVI. However, the overall survival of patients with MT carcinoma was not significantly different from that of patients with IT or DT carcinomas ( P= 0.104). Conclusions: The presence of MT EGC carries a higher risk of LNM compared to IT or DT carcinomas. Therefore, MT carcinomas should be managed with gastrectomy that includes lymph node dissection instead of endoscopic resection.
Thromboembolic events (TE) among patients with metastatic pancreatic ductal adenocarcinoma (mPDA) after chemotherapy (Chemo).
Authors: Lyman Gary H. , Schabert Vernon F , Philip Philip Agop , Stokes Michael , Bhurke Sharvari , Kuderer Nicole M , Qadan Ammar , Khorana Alok A. 
Published: March 2017

280 Background: Clinical trials suggest that patients with mPDA are at high risk of TE from both disease and treatment. TE rates and anticoagulant use among mPDA patients after first line chemo were investigated. Methods: Medicare beneficiaries enrolled in parts A, B, and D; diagnosed with mPDA; aged ≥ 65 years; and starting chemo between 1/1/2007 and 12/31/2012 were obtained from Surveillance, Epidemiology, and End Results (SEER)-Medicare data. Eligible patients were enrolled from 12 months before chemo and followed until death, post-chemo disenrollment, or 12/31/2012. Arterial (ICD-9 410-411, 433-434), venous (ICD-9 415.1x, 453.4x, 453.8x, 453.9), and total TE were defined as ≥ 2 outpatient diagnoses ≥ 30 days apart, one inpatient diagnosis, or one outpatient diagnosis followed by outpatient anticoagulants within 90 days. Post-chemo TE incidence was calculated as the number of first events per 100 person-years (PY) for patients with and without TE 12 months before chemo. Time from chemo to first TE was estimated using the Kaplan-Meier (KM) method. Results: Among 1,308 eligible patients, mean age was 74 years [range 65-93]; 56% were female; 85% had no prior TE. Overall, 419 (32%) had a TE after chemo including 121 (9%) arterial and 363 (28%) venous TE. The table shows incidence, and time to TE for those with and without prior TE. Outpatient anticoagulants were prescribed for 276 (25%) patients with no prior TE and 110 (57%) patients with prior TE. Table. TE incidence and time to TE among mPDA patients after chemo Conclusions: mPDA patients face a substantial risk of TE after chemo, with nearly one-third of patients without prior TE and one-half of patients with prior TE experiencing events during treatment. These high rates of TE indicate the importance of conducting risk assessments for preventive measures early during a patients’ care.[Table: see text]
Adjuvant therapy in stage II pancreatic cancer: A National Cancer Database analysis.
Authors: Ahmed Aabra , Walters Ryan W , Malouff Timothy Dean , Krishnan Mridula , Jabbari Javaneh , Silberstein Peter T. 
Published: March 2017

283 Background: Oldfield et al (2015) showed the conflicting evidence regarding the effect of adjuvant chemotherapy vs. chemoradiation in pancreatic cancer. Using patients identified by the National Cancer Database (NCDB), we are the largest study to compare survival in stage II pancreatic cancer patients who received adjuvant chemotherapy, chemoradiation, radiation, or no adjuvant therapy. Methods: We identified 65,091 patients with stage II pancreatic cancer who received surgery only or surgery in combination with chemotherapy, radiation, or chemoradiation. Between-therapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p < .05 indicated statistical significance. Results: Patient characteristics were similar between groups; although, patients receiving chemoradiation were younger, had fewer comorbidities, and were more likely to have private insurance compared to all other therapy groups. Statistically significant survival differences were indicated between all therapy groups (all adjusted p< 0.05), as patients receiving chemoradiation had the longest survival followed by patients receiving chemotherapy, patients receiving radiation therapy, and patients receiving no adjuvant therapy (median survival = 22.5, 19.6, 16.9, 14.8 months, respectively). When examining other variables, patients living in an area with a median income < $43,000 were 14% more likely to die compared to patients in an area with a median income ≥ $63,000 (p < 0.001) and those with no comorbidities were 19% less likely to die than patients with two or more comorbidities (p < 0.001). Conclusions: Our data suggests that adjuvant therapy improves median and 3-year survival compared to no adjuvant therapy. Of all adjuvant therapies examined, adjuvant chemoradiation was associated with the greatest increase in survival, followed by adjuvant chemotherapy. Table 1: Median survival and survival rates of stage II pancreatic cancer [Table: see text]
A phase I/II trial of MEK162 in combination with gemcitabine (G) and cisplatin (C) for patients (pts) with untreated advanced biliary cancer (ABC).
Authors: Lowery Maeve Aine , O'Reilly Eileen Mary , Harding James J. , Yu Kenneth H. , Cercek Andrea , Hollywood Ellen , Salehi Erica , Margona Ezra , Bradley Mikaela , Witter Trevor , Gerst Scott R. , Capanu Marinela , Saltz Leonard , Abou-Alfa Ghassan K. 
Published: March 2017

290 Background: Activating mutations in the RAS/RAF/MEK/ERK signaling pathway are commonly found in ABC. MEK162 is an oral, selective small molecule inhibitor of MEK1/2; single agent activity of MEK162 in ABC has previously been observed. Preclinical data support anti-tumor synergy for MEK inhibition (MEKi) when combined with G & C, only when MEKi is held for 2 days prior to and on day of each G and C infusion. Methods: A Single arm, non-randomized, open-label, phase I/II,evaluated oral MEK162 twice daily with G and C IV infusions day 8 and 15 of a 21 day cycle. MEK162 was. Eligibility criteria were: untreated ABC, with advanced measurable disease, ECOG 0-1, adequate hematologic, renal, hepatic and cardiac function. The primary endpoints were to determine the MTD (phase 1); and 6 month PFS and response rate (RR) (phase II). Tumor tissue for targeted somatic mutational sequencing was evaluated. Results: Between 09/13 and 09/15, 12 pts were enrolled on phase 1, the MTDs were MEK162 45mg PO BID, in combination with G 800 mg/m2 and C 20mg/m2. 35 pts evaluable for primary endpoint of phase II (29 treated on phase II & 6 pts treated at MTD in phase 1): Male = 19, median age 63 years (range 48- 77). Cholangiocarcinoma (CC) = 24, and gallbladder adenocarcinoma (GB) = 11. Median overall survival was 21 months (95% CI 11- NA), median PFS 6 months (95% CI 4-14). Molecular profiling using MSK-IMPACT 410 gene panel was feasible in 29 pts; aberrations in the RAS-RAF-MEK-ERK pathway were notable in responding pts including mutations in PIK3CA, AKT2, PIK3CG, KRAS, BRAF and MAP3K1. Overall RR was 36%, GB 45%, CC 32%. Two pts had CR, two pts remain on study > 24 months, currently on MEK162 alone. Conclusions: The MTDs were MEK162 45mg PO BID, in combination with G 800 mg/m2 and C 20mg/m2.. Significant activity of the combination was noted in select pts with prolonged and complete response to treatment. Molecular profiling of BTC may facilitate selection of pts for further development of the combination. Clinical trial information: NCT01828034.
A phase IB study of CX-4945 in combination with gemcitabine plus cisplatin in the frontline systemic treatment of patients with advanced cholangiocarcinoma.
Authors: Borad Mitesh J. , Hubbard Joleen Marie , Oh Do-Youn , Rha Sun Young , Mody Kabir , Lim John K.C. , Richards Donald A. 
Published: March 2017

294 Background: CX-4945 is a first-in-class casein kinase-2 (CK2) threonine kinase small molecule inhibitor. CK2 is pleiotropic and regulates key cellular processes such as proliferation and DNA damage repair, and has been shown to enhance efficacy of gemcitabine (G) and cisplatin (C) in cell line and xenograft CCA model systems. A Phase IB study of G+C with CX-4945 was conducted in advanced cholangiocarcinoma (CCA) patients. Methods: A multi-center “3+3” dose escalation study was conducted in advanced CCA patients. Eligible patients had ECOG PS 0-1 and adequate hematologic, hepatic, and renal function. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). Secondary endpoints included pharmacokinetic (PK) analyses, overall toxicity evaluation and preliminary assessment of efficacy. Routine clinical dosing for G (1000 mg/m2) and C (25 mg/m2), both on days 1 and 8 every 21 days, was used. Dose escalation cohort were CX-4945 given twice daily on days 0,1,2 and 7,8,9 at 200 mg (DL1), 400mg (DL2), 600 mg (DL3), 800 mg (DL4) and 1000 (DL5) mg. NCI CTCAE v4.03 was used for toxicity assessment and RECIST v1.1 for efficacy evaluation. Results: Nineteen patients were enrolled (DL1:n = 3; DL2:n = 4 DL3:n = 3; DL4:n = 4; DL5:n = 5). No dose limiting toxicities were encountered. MTD and RP2D were ascertained to be DL5. No grade 3 or 4 toxicities at prevalence > 10% were encountered and the overall toxicity profile of the combination was reflective of standard G+C toxicity profile. At data cut-off, preliminary efficacy evaluation demonstrated disease control rate (CR+PR+SD) of 64% (PR:32%, SD:32% and CR:0%), along with median progression-free survival (PFS) of 5 months (range 0-14 months). PK analyses showed no evidence of drug-drug interactions between G, C and CX-4945. Conclusions: RP2D for G+C with CX-4945 is DL5 (CX-4945 dosed on days 0,1,2 and 7,8,9 at 1000 mg PO bid with standard G and C dosing). Preliminary clinical efficacy and tolerability of the regimen support planned controlled, randomized Phase 2 evaluation. Clinical trial information: NCT02128282.
Evaluation of efficacy of oral administration of pro-drug of triptolide against pancreatic cancer.
Authors: Dudeja Vikas , Sharma Nikita , Modi Shrey , Merchant Nipun B. , Vickers Selwyn M. , Banerjee Sulagna , Saluja Ashok 
Published: March 2017

296 Background: Pancreatic cancer is an aggressive disease. The current chemotherapy only marginally increases the survival of patients with PDAC. Hence there is an urgent need for novel therapies. We have shown that minnelide, a pro-drug of triptolide which is currently in phase I trials, when administered intra-peritoneally is very effective against pancreatic cancer in multiple animal models. In the current study we evaluated the efficacy of oral minnelide against pancreatic cancer, alone or in combination with standard therapy in PDAC. Methods: Xenograft, subcutaneous and orthotopic models were established using S2-VP10 and MIA PaCa-2 cell lines. Minnelide was used in doses ranging from 0.15-0.6 mg/kg/day either oral or i.p. and standard chemotherapy was gemcitabine 250 mg/kg/week + nab-paclitaxel 25 mg/kg/week. The tumor burden was compared between various treatment groups. Results: Minnelide i.p significantly decreased tumor mass in MIA PaCa-2 derived tumors and oral administration had equipotent effects. In the S2-VP10 model, combination of low doses of orally administered minnelide with gemcitabine + nab-paclitaxel was significantly more effective in decreasing the tumor burden leading to an increased survival of tumor bearing mice when compared with either therapy alone (p < 0.05). Combination therapy significantly reduced cancer-related morbidity by decreasing ascites and metastasis. Conclusions: Oral administration of minnelide is effective against pancreatic cancer at doses which have been shown to be safe in phase I clinical trial. Oral minnelide has great potential to emerge as novel therapy for pancreatic cancer.
RNA profiling of neuroendocrine tumors (NETs) to define new targets and mechanisms of progression.
Authors: Vijayvergia Namrata , Peri Suraj , Devarajan Karthik , Pei Jianming , Gong Yulan , Cohen Steven J. , Astsaturov Igor A. , Engstrom Paul F. 
Published: March 2017

302 Background: NETs lack mutations in the “classical” signaling pathways but share mutations in regulators of gene expression (Jiao; 2011). We compared gene expression in PD & WD NETs to identify novel targets and biomarkers of differentiation. Methods: High quality RNA, extracted from paraffin blocks of deidentified NETs under an IRB-approved protocol, was profiled using a 770 gene panel (nCounter PanCancer pathway, Nanostring Technologies). The resulting data was used to identify the differentially expressed genes between PD and WD NETs using limma software (Ritchie; 2015). Gene Set Enrichment Analysis (Subramanian; 2005) identified differential pathway enrichment by calculating a Normalized Enrichment Score (NES). Results: Analysis of 16 PD and 23 WD NET samples identified 154 genes as extreme outliers ( > 2 fold up/downregulation between the subtypes). Compared to WD NETS, drug targets of interest overexpressed in PD NETs were histone lysine methyltransferase EZH2, and a cell cycle regulator CHEK1 (6.5x and 8.1x, respectively, p < 0.001). In contrast, serine/threonine protein kinase PAK 3 was upregulated in WD (10.6x, p < 0.001). These and other biomarkers will be further validated by immunolabeling of tissue sections. We also found differential enrichment of canonical pathways in PD versus WD NETs (table). Conclusions: Extreme outlier transcripts identified in PD & WD NETs support investigation of inhibitors of EZH2 (e.g. EPZ6438) and CHEK1 (e.g. LY2606368) in PD and PAK3(e.g. FRAX597) in WD NETs. Genes involved in cell cycle regulation and DNA repair in PD NETs and calcium / G protein coupled receptor signaling in WD NET account for biological differences between the 2 molecular subtypes and warrant future investigation as classifiers for NETs. Our findings provide mechanistic insights into the biology of NET and targets for therapy with direct clinical implications.[Table: see text]