bluuebunny/crossref_metadata_2025_split huggingface dataset:
Doxorubicin drug eluting beads transcatheter chemoembolization (DEB TACE) in patients with large hepatocellular carcinoma (HCC): Overall survival and a multivariate analysis (MVA) of prognostic factors.
Authors: Prajapati Hasmukh J. , Spivey James R. , El-Rayes Bassel F. , Kauh John S. , Kim Hyun Sik 
Published: March 2020

e15033 Background: To investigate the prognostic factors (PFs) associated with survival after DEB TACE in patients (pts) with at least > 5cm sized index HCC (iHCC). Methods: Consecutive pts with at least > 5cm sized iHCC, who received DEB TACE over last 82 months, were studied. Median overall survivals (mOSs) were analyzed according to different parameters from 1st DEB TACE. Kaplan Meier estimator by log rank test and Cox proportional Hazard model (for MVA) were used survival analyses using v20 SPSS. Results: 332 DEB TACEs (mean 3, medium 2) were performed in 112 pts (mean 62.1 years, SD 12), who had at least >5cm sized iHCC (mean 9.5 cm, SD 3.7). MOS from diagnosis and DEB TACE were 14.3 months (m) and 9.4 m respectively. MOS were 31.9 m, 11.1 m and 2.8 m in pts who received > 4, 2-4 and a 1 DEB TACEs respectively (p<0.001). Etiological factors for HCC were hepatitis C virus (54.4%), hepatitis B virus (12.5%), chronic alcoholism (7.1%), other causes of chronic liver disease (17%) and unknown with no chronic liver disease (9%); mOS were 8.8 m, 4.4 m, 5.8 m, 27 m, and 9.4 m respectively (p=0.01). MOS in pts with Child-Pugh Class A (58.9%), B (34.8%) and C (6.3%) were 17.2 m, 5.8 m and 1.6 m respectively (p<0.001). MOS in pts with BCLC stage B (17%), C (69.6%) and D (13.4%) were 20.9 m, 9.4 m, and 3.4 m respectively (p=0.003). 46.4% of pts had portal vein thrombosis (PVT) with mOS of 5.4 m vs. 17.1m in pts without PVT (p=0.006). Pts with serum alfa feto protein (sAFP) level>400 ng/dl (43.7%) had mOS of 5.4 m vs. 16.6 m in pts with sAFP<400ng/dl (p=0.008). 32.1% of pts received sorafenib systemic chemotherapy; mOS were 13.3m vs. 7.6m who did not receive the sorafenib (p=0.2). Pts with >5 HCCs (20.5%) had mOS of 5.4m vs. 13m in pts who had <5 HCCs (p=0.009). The following variables were independent significant PFs of survival on MVA: Child-Pugh class, etiology, number (no) of DEB TACEs, presence of vascular invasion and ECOG PS. Conclusions: Higher number of DEB TACE treatments correlates independently to improved OS in patients with at least >5cm sized index HCC. Other independent PFs of survival were etiology, Child-Pugh class, no of HCC tumors, ECOG PS and PVT.
Patterns of recurrence after neoadjuvant docetaxel, cisplatin, and 5FU combined with resection and extended lymphadenectomy for locally advanced esophagogastric adenocarcinoma.
Authors: Ferri Lorenzo , Alcindor Thierry , Ades Steven , Aloraini Abdullah , Vanhuyse Marie , Asselh Jamil , David Marc , Thirlwell Michael P. 
Published: March 2020

e15044 Background: We have previously identified Docetaxel, Cisplatin, and 5FU (DCF) as a highly effective regimen in the neoadjuvant setting for locally advanced adenocarcinoma (ADC) of the esophagus and esophago-gastric junction (EGJ). However there is ongoing debate whether chemotherapy alone provides adequate local or regional control. We hypothesized that DCF combined with enhanced local surgical control would result in a low rate of local or regional recurrence. Methods: A prospective entered database of all esophageal/EGJ ADC pts resected at a high volume referral center was reviewed for cases treated with neoadjuvant DCF (Docetaxel 75mg/m2, Cisplatin 75mg/m2, 5FU 750mg/m2x120 hrs CIV) Q3weeks x3, followed by en-bloc resection with extended lymphadenectomy (D2). Follow up included physical exam Q3m x 2 yrs then Q6m, and endoscopy and CT chest/abdo/pelvis performed Q6 m. Recurrence was defined as: Local = biopsy on endoscopy; Regional = regional lymph nodes; Distant = distant organ or non-regional lymph nodes. Data presented as Median (Range). Results: Of 281 pts in the database, 89 (75%male, 63yrs(24-80)) underwent pre-op DCF and resection for locally advanced ADC (cT3 93%;cN+ 73%) of the EGJ (51%) or distal esophagus (49%) from 3/07-10/12. After overall follow-up of 37(6-72) months, 37 (42%) have recurred at 15(6-33) months. Sites of recurrence include Distant only in 29/37, Regional only in 5/37, and Regional and Distant in 3/37. First site of distant recurrence was peritoneum (14/37), liver (10/37), non-regional lymph nodes (10), brain/ovary/pleura (2 each), and bone(1). No patient had local recurrence alone. 3/5 patients with regional recurrence underwent salvage chemoradiotherapy and are alive without disease at 36 months (30-47) after recurrence. Conclusions: En-bloc resection with extended lymphadenectomy after DCF for locally advanced ADC of the esophagus and EGJ is associated with a low rate of local and regional recurrence. As vast majority of recurrences are distant, our data supports the notion that efforts to improve outcomes in these pts should concentrate on enhancing systemic, rather than local, therapy.
Expression of stem cell markers in pancreatic ductal adenocarcinoma and clinical relevance.
Authors: Andrikou Kalliopi , Faloppi Luca , Loretelli Cristian , Mandolesi Alessandra , Bearzi Italo , Cascinu Stefano 
Published: March 2020

e15058 Background: Emerging evidence has suggested that malignant tumors are heterogeneous and that are composed of a small subset of distinct cancer cells (usually defined by cell surface marker expression) that are responsible for tumor initiation and propagation, termed cancer stem cells. These cancer stem cells (CSCs), or tumor-initiating cells (TICs), exhibit properties of normal stem cells and are associated with resistance to current therapies. It was found that human pancreatic cancer has shown a population of cancer stem cells that have aberrantly activated developmental signaling pathways, are resistant to standard chemotherapy and radiation, and have up-regulated signaling cascades that are integral for tumor metastasis. The aim of our study is to investigate the prognostic implication of cancer stem cell markers in pancreatic ductal adenocarcinoma. Methods: In 43 histological samples of pancreatic ductal adenocarcinoma were performed molecular biology assessment of CD 24, CD44, CD133, CD166, OCT3/4, LGR5. Results: At univariate analysis patients with an overexpression of CD44, CD133, OCT3/4 showed a worse prognosis in terms of overall survival (respectively: p=0.031; p=0.014; p=0.001). At multivariate analysis OCT3/4 resulted to be independent factor influencing outcome (HR=0.23). Patients with overexpression of all factors seem to have a worse OS compared to patients expressing only two, one or none (8.6 vs. 15.6 vs. 18.0 vs. 59.9 mts; p=0.006). Conclusions: Our data suggest that the presence of cancer stem cells could be linked with tumor aggressiveness and patients’ survival. This finding could drive therapeutic decision towards less or more intensive treatment.
Cdc7 inhibition as a novel approach for pancreas cancer therapy.
Authors: Frattini Mark G. , Regales Lucia , Santos Ruth , Carrillo Diana 
Published: March 2020

e15059 Background: Pancreatic cancer is the fourth leading cause of cancer death in the USA. In 2012, 43,920 people will be diagnosed and 37,390 people will die of this disease. 95% of tumors reveal loss of the p16 protein, a regulator of the G1 to S phase transition. Cdc7 is a conserved kinase required for the initiation of DNA replication, is a target of the S-phase checkpoint, and has a role in controlling the DNA damage response. Downregulation of Cdc7 kinase activity resulted in slowing of S-phase and cell cycle arrest followed by accumulation of DNA damage. Cdc7 has been shown to be over-expressed in many different tumors including the majority of solid and liquid tumors. In our laboratory a novel natural product small molecule inhibitor (MSK-777) has been identified, developed and shown to be efficacious in cell based cytotoxicity assays and multiple animal models of cancer. Methods: We have examined the efficacy of Cdc7 kinase inhibition as a therapeutic approach for pancreatic cancer by examining the sensitivity of MSK-777 in Capan-1, BxPC3, and PANC-1 cell lines. These cells were treated with MSK-777, control (DMSO), or hydroxyurea and collected for viable cell counts, fluorescence-activated cell sorting (FACS), and western blotting. Results: Cell viability analyses revealed that MSK-777 had a dramatic effect after 24 hours, reducing cell viability to less then 20% in BxPC3 cells. FACS results demonstrated that MSK-777 exposure resulted in cell cycle arrest at G1/S in Capan-1 and PANC-1 cells by 48 hours while BxPC3 cells showed a significant sub-G1 population by 24 hours, indicating apoptotic cell death. Western blotting showed that in BxPC3 cells phosphorylation of the mini-chromosome maintenance 2 protein (Mcm2) disappeared by 24 hours, indicating inactivation of the helicase that unwinds the strands of DNA during replication. Western blots of Capan-1 and PANC-1 cells showed lower levels of phosphorylated Mcm2 by 48 hours. Conclusions: We are currently examining the efficacy of MSK-777 in mouse models of orthotopically injected pancreatic cancer cells. Based on these collective results, inhibition of Cdc7 kinase activity with MSK-777 represents a novel and promising therapy for this deadly disease.
Assesment of SOX-17 gene promoter hypermethylation in hepatocellular carcinoma.
Authors: Chelis Leonidas , Balgouranidou Ioanna , Koukaki Triantafyllia , Michailidis Prodromos , Christakidis Evagelos , Xenidis Nikolaos , Amarantidis Kiriakos , Trypsianis Grigorios , Kakolyris Stylianos 
Published: March 2020

e15063 Background: SRY-box containing gene 17 (SOX-17) is implicated in the WNT/β-catenin pathway and acts as a tumor suppressor gene inhibiting the transcription of activated β-catenin. WNT oncogene plays a crucial role in liver carcinogenesis and has been shown to correlate with poor survival and aggressive behavior in hepatocellular carcinoma (HCC). Silencing of SOX-17 gene through promoter hypermethylation results in WNT overexpression. Tumor-related cell free DNA (cfDNA), circulating in the blood of cancer patients can be used for the detection of methylation status of several genes. Therefore, we examined SOX-17 methylation in the blood of HCC patients and correlated it with the outcome. Methods: Patients diagnosed with HCC were eligible. cfDNA from 87 patients (N=87) was isolated from 200 μL serum before any treatment. After DNA extraction, all samples were subjected to a sodium bisulfite conversion reaction. Methylation specific polymerase reaction (MSP) for SOX17 promoter methylation was performed using specific primer pairs for both the methylated and unmethylated promoter sequences. Results: According to BCLC staging system, our patients were staged as A=5 (5.6%), B=15 (17.2%), C=67 (77%) respectively. SOX-17 methylation was detected in 58 (66.7%) patients while 29 (33.3%) had a non-methylated gene. The methylated form of the gene was significantly correlated with an impaired performance status (PS) of 2-4 (p=0.021) and with extrahepatic spread of the disease (p=0.036). No correlation was detected for stage, Child-Pough score of cirrhosis, or underlying cause of HCC. The overall survival (OS) was 14 months for the non-methylated and 5 months for the methylated gene, respectively (p= 0.0062). Sixty three patients received sorafenib as 1st line treatment. The OS was 15 months for patients with the non-methylated and 6 months for patients with the methylated gene, respectively (p= 0.012). In the multivariate analysis for OS, SOX-17 methylation status along with PS remained significant (p=0.04) Conclusions: Assessment of SOX-17 promoter hypermethylation in the peripheral blood is feasible. SOX-17 gene methylation is a frequent event in HCC and seems to correlate with a poorer outcome.
Pharmacodynamic separation (PDS) of gemcitabine (Gem) and the epidermal growth factor receptor (EGFR) inhibitor erlotinib (E) in patients (Pts) with advanced pancreatic cancer: Phase II results.
Authors: Semrad Thomas John , Lenz Heinz-Josef , Gong I-Yeh , Tanaka Michael S. , Eddings Courtney , Mahaffey Nichole , Mack Philip C. , Beckett Laurel , Lara Primo 
Published: March 2020

e15073 Background: Continuously dosed E given concurrently with Gem results in only a modest survival improvement in pts with advanced pancreatic cancer. Preclinical data suggest that there is antagonism between chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) when these are delivered concurrently due to cell cycle effects. Work by our group and others has shown that EGFR TKIs induce cytostasis due to G1 arrest, which reduces subsequent cell cycle phase-dependent activity of chemotherapy. We tested a PDS approach for E + Gem as a means of overcoming the hypothesized negative interaction of EGFR TKIs and chemotherapy. Methods: Pts with measurable, previously untreated locally advanced unresectable/metastatic pancreatic cancer with adequate organ function and PS 0-2 were eligible. Tumor tissue was collected for molecular studies. PDS Regimen: Gem 1000 mg/m2 IV days 1, 8, 15, and E 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle. Primary endpoint was PFS; secondary endpoints included response rate (RR) and safety. To have 80% power at 5% significance, 70 pts were planned to detect an increase of PFS from 3.75 to 5.25 months. The study was terminated due to funding considerations. Results: 30 pts enrolled with median age 67 years (range 46-84); PS: 0 (23%), 1 (47%), and 2 (30%); locally advanced (13%) & metastatic (87%). Median PFS was 2.07 months (95% CI; 1.87 – 5.50 months). Median OS was 5.67 months (95% CI; 2.83 – 11.87 months). Median cycles completed were 2 (range 0-8). Two pts withdrew consent in the first cycle without progression and were not evaluable for response. RR was 11% (3 PRs); DCR was 46%. Grade 3/4 adverse events occurred in 63% of pts; the most common were neutropenia (23%), fatigue (13%), anemia (10%), thrombocytopenia (10%), rash (10%), nausea (10%), and diarrhea (10%). Conclusions: Although Gem and E in a PDS dose-schedule was feasible & tolerable in pts with advanced pancreatic cancer, no signal for increased efficacy was seen (compared to historic controls) in this molecularly unselected cohort. Correlative studies to identify potential molecular biomarkers of benefit are ongoing and will be presented. Clinical trial information: NCT00810719.
Phase I study of combination of pasireotide (SOM 230) plus gemcitabine in metastatic pancreatic cancer (MPC).
Authors: Kim Richard D. , Jump Helen , Chen Dung-Tsa , Fulp William J. , Shibata David , Siegel Erin , Springett Gregory M. 
Published: March 2020

e15075 Background: For the past decade, gemcitabine (GEM) has been considered the standard chemotherapeutic agent in the treatment of MPC. SOM-230 is a multi-targeted somatostatin (SST) receptor (sst1,2,3 and 5) analog with five times the affinity of other SST receptor analogs and a potent inhibitor of insulin growth factor -1(IGF-1). SST receptors and IGF receptors are highly expressed in pancreatic cancer therefore potentially making it a valuable target. Methods: Patients with previously untreated MPC and ECOG PS 0-1 were eligible for the trial. A 3+3 dose escalation design was used. Patients with MPC received GEM 1000 mg/m2 (30-min, once-weekly IV infusion for 3 out of 4 weeks) and SOM 230 according to dose escalation. 2 dose levels (DL) were planned. (40mg and 60 mg IM once a month). Following MTD determination the plan was to expand the cohort to 10 more patients to assess efficacy. In the expanded cohort plasma levels of IGF-I, IGFBP (insulin growth factor binding protein)-1, and IGFBP-3 were measured at baseline and with each restaging CT scan. Results: 20 patients were enrolled with 16 patients evaluable for safety and efficacy. 3 patients were each enrolled in DL1 and DL2. No dose limiting toxicities related to SOM 230 were observed at any dose level. MTD was not reached. Therefore cohort at 60mg was expanded to 10 patients to assess efficacy. Median age was 65.5 years; 6 males and 10 females. Most common grade 3 or 4 toxicities were hyperglycemia (n=5), increased bilirubin (n=2), neutropenia (n=1), thrombocytopenia (n=1) and fatigue (n=1). Two of 16 evaluable pts (12%) had confirmed partial responses (PR), and 9 had stable disease (56%) as best response. Median PFS for all pts was 4.1 months and overall survival was 8.0 months. As of Feb 2nd2013 there are 3 patients who are still actively receiving treatment on the trial. One patient still has stable disease after 11 months. Plasma levels of IGF-I, IGFBP-1, and IGFBP-3 were measured and will be presented. Conclusions: SOM 230 (60 mg IM monthly) plus gemcitabine was well tolerated in pts with MPC. Preliminary efficacy in a cohort of 16 pts with MPC looks promising and warrants further evaluation Clinical trial information: NCT01385956.
Use of phosphoprotein profiling with high-density fluorescence protein microarray to reveal a response predictor to a multikinase inhibitor sorafenib.
Authors: Yamada Tesshi , Masuda Mari , Chen Wei-Yu , Chen Chi-Long , Honda Kazufumi 
Published: March 2020

e15080 Background: The efficacy of sorafenib in patients with unresectable hepatocellular carcinoma (HCC) has been revealed in the recent phase III SHARP (Sorafenib HCC Assessment Randomized Protocol) clinical trial, but only a small proportion of patients achieved the anticipated therapeutic outcomes. It is essential to identify biomarkers that will discriminate such patients. Methods: We newly developed high-density fluorescence reverse-phase protein arrays and used them to profile the phosphorylation status of 180 signaling molecules in the 120 pathways registered on the NCI-Nature curated database in 23 HCC cell lines with different sensitivities to sorafenib. Results: Among the 180 signaling nodes, we found that the level of ribosomal protein S6 phosphorylated at serine residues 235/236 (p-rpS6 S235/236) was the most significantly correlated with the sensitivity of HCC cells to sorafenib. The high expression of p-rpS6 S235/236 was confirmed immunohistochemically in biopsy samples obtained from HCC patients who responded poorly to sorafenib. Sorafenib-resistant HCC cells showed constitutive activation of the mammalian target of rapamycin (mTOR) and/or the mitogen-activated protein kinase (MAPK) pathways downstream of c-RAF. Conclusions: The present results indicate that p-rpS6 S235/236 is a potential predictor of unresponsiveness to sorafenib. Cross-talk between the mTOR and MAPK signaling pathways in sorafenib-resistant HCC cell lines was also revealed. A combination of mTOR and MAPK inhibitors may improve the efficacy of molecular targeting therapy against HCC.
Resminostat in advanced hepatocellular carcinoma (HCC): Overall survival subgroup analysis of prognostic factors in the SHELTER trial.
Authors: Bitzer Michael , Ganten Tom M. , Woerns Marcus A. , Siveke Jens T. , Dollinger Matthias M. , Scheulen Max E. , Wege Henning , Giannini Edoardo G. , Cillo Umberto , Trevisani Franco , Santoro Armando , Montesarchio Vincenzo , Mais Anna , Hauns Bernhard , Asche Julia , Herz Thomas , Pegoraro Stefano , Ammendola Aldo , Henning Stefan W. , Hentsch Bernd ,   SHELTER Study Group
Published: March 2020

e15088 Background: Previously published results of the phase I/II SHELTER study demonstrated efficacy and safety of the novel pan-HDAC inhibitor resminostat in second-line treatment of HCC patients (pts) who had progressed under first-line sorafenib. As patient baseline characteristics might influence treatment outcome, an analysis of their potential influence on overall survival (OS) was performed. Methods: 45 pts with advanced-stage HCC and centrally confirmed radiologic progression under first-line sorafenib were included in a multi-center, two-arm trial. Resminostat was administered either alone or in combination with sorafenib. A Cox proportional-hazards model was used to evaluate the interaction between baseline characteristics and the effect of the two treatment groups on overall survival. Results: In the combination group, pts with Child-Pugh-A, ECOG 0 or absence of vascular invasion had a statistically significant lower risk of death compared to pts with Child-Pugh-B (HR 0.19, 95% CI 0.06-0.55), ECOG 1 (HR 0.15, 95% CI 0.05-0.44), or vascular invasion (HR 0.37, 95% CI 0.15-0.93), respectively. For pts with BCLC-B there was a strong trend, although not statistically significant, of a lower risk of death when compared to pts with BCLC-C (HR 0.43, 95% CI 0.13-1.49). Etiology, prior TACE therapy, extrahepatic spread and interval between first- and second-line treatment had no impact on overall survival in this study. Similar findings were observed in the monotherapy group. Comparing the impact of these baseline characteristics in the combination and monotherapy group, no statistically significant different influence on OS between both treatment groups was observed. Conclusions: Resminostat in combination with sorafenib provides a substantial OS benefit (median OS of 8.1 months) for advanced HCC patients who had developed progressive tumor disease under first-line sorafenib therapy. Subgroup analysis of patient baseline characteristics revealed a significant influence of Child-Pugh index, ECOG classification, and vascular invasion on overall survival, whereas e.g. the interval between first- and second-line treatment had no impact on overall survival. Clinical trial information: NCT00943449.
Recurrent anal squamous carcinoma: Is HPV a risk factor?
Authors: Letendre Caroline , Aubin Francine , Ayoub Jean-Pierre M. , Letourneau Richard , Lougnarath Rasmy , Richard Carole S. , Delouya Guila , Donath David , Lavertu Sophie , Campeau Marie-Pierre , Gorska Isabelle , Soucy Genevieve , Nguyen Bich , Tehfe Mustapha Ali 
Published: March 2020

e15094 Background: Anal squamous carcinoma (ASC) is a rare cancer, representing only 1.5 to 2% of all gastrointestinal (GI) malignancies. Combined chemo-radiotherapy therapy (CRT) is the treatment of choice with a response rate of 80% and recurrence rate of 10 to 15%. HPV is a risk factor for anal cancer but its role in cancer recurrence is less clear. We conducted a retrospective study to analyze clinical outcome of ASC patients in function of their HPV status. Methods: Patients with non-metastatic ASC treated between 2005-2011 at the Centre Hospitalier de l’Université de Montréal were eligible. Patient characteristics, clinical outcomes, and tumoral HPV status were retrospectively identified. Results: Seventy patients (M:31; F:39) were included in the analysis. The median age of patients was 51 years. Patient and tumor characteristics are shown in the Table. CRT was done in 57 patients. Median follow-up was 37.6 months. Eleven patients had recurrence of whom 10 were HPV-positive. Median TTR was 13.2 months. The 3 deaths related to cancer occurred during the first year of diagnosis. The 3 year overall survival was 90.08%. In multivariate analysis neither the advanced stage of disease nor the HPV-positive status had a statistically significant impact on relapse. Conclusions: In this small cohort, we found a high prevalence of HPV positivity in ASC but HPV infection couldn’t be identified as a risk factor for ASC relapse. Inclusion of men in the HPV vaccination program may help in reducing HPV related ASC. [Table: see text]