bluuebunny/crossref_metadata_2025_split huggingface dataset:
VTE among pancreatic cancer and its possible risk factors among metastatic pancreatic cancer (mPC): Experience at Fox Chase Cancer Center.
Authors: Pandey Ramesh Kumar , Sorice Kristen , Gou Jiangtao , Lynch Shannon M. , Blumenreich Aryeh , Cheema Khadija , Nagappan Lavanya , Dotan Efrat , Vijayvergia Namrata 
Published: January 2019

232 Background: The incidence of VTE is relatively high among mPC pts, upto 57%. It is associated with higher health care burden and mortality. We evaluated the mPC pts treated at a single academic center from 2010-16 for prevalence of VTE, its impact on survival and possible risk factors. Methods: Medical charts of mPC pts treated at a single academic center were analyzed retrospectively for VTE diagnosis, overall survival and potential risk factors for VTE development. The factors considered were: age, sex, stage, body mass index, smoking status, surgery, performance status (PS), Charlson comorbidity index (CCI) and treatment. Logistic regression was used to identify the factors correlating with VTE and Cox Proportional Hazard model was used to evaluate overall survival (OS) differences between those with VTE (Gp A) and those without VTE (Gp B). Results: Out of the 439 mPC pts (52% males, 86% with PS0-1, 63% with stage IV at diagnosis), 127 (29%) were in Gp A and 312 (71%) in Gp B. The groups were well balanced with respect to all factors except age (median age 67 Gp A; 65 in Gp B, p = 0.04). 2.3 % of pts in Gp A and 4.8 % pts in Gp B were on anticoagulation for reason other than VTE treatment. Within Gp A, 55% developed VTE after diagnosis of metastasis. A clear separation of the survival curves noted beyond the median OS (9 m, P = 0.02), favoring GpB. Statistically significant factors associated with risk of VTE included advanced stage at diagnosis (P = 0.004) and worse PS (P = 0.005). Treatment regimen used and CCI didn’t correlate with the risk of development of VTE. Conclusions: The incidence rate of VTE in our patients is lower than published literature, yet the diagnosis of VTE was associated with worse OS. Most cases occurred after the diagnosis of metastatic disease. The higher use of anticoagulants for other medical causes may be contributing to a lower incidence of VTE in mPC. These findings need prospective Validation.
Factors associated with biopsy diagnosis of hepatocellular carcinoma.
Authors: Rho Young soo , Acoba Jared David 
Published: January 2019

235 Background: Hepatocellular carcinoma (HCC) is one of the few cancers that can be diagnosed based on imaging findings. Although not always mandatory for diagnosis, biopsy (Bx) can confirm HCC and its histologic subtype. We have demonstrated that Bx is associated with worse survival compared to imaging diagnosis in a multivariate analysis. In turn, factors associated with undergoing a Bx diagnosis were examined. Methods: We obtained demographic, diagnostic, and treatment data of 171,013 patients diagnosed with HCC between 2004–2015 from the National Cancer Database. Binary logistic regression examined factors associated with Bx. Variables analyzed included race, sex, age, comorbidity, facility type, insurance, tumor size, presence of metastatic disease, alpha fetoprotein, total bilirubin, year of diagnosis and administration of therapy. Analysis was performed using SPSS v25. Results: We included 160,517 patients for the final analysis. The median age was 62 (18–90), 73.9% were male and 74.1% were white. 11.5% of tumors were 2 cm or smaller and 13.7% of HCC were metastatic. 78,485 (47.7%) underwent Bx. In a multivariate model, black patients (OR 1.093; 95% CI: 1.061-1.126), older patients (OR 1.579; 95% CI 1.537–1.622), larger tumor size (OR 3.208; 95% CI: 3.085–3.335), private (OR 1.129; 95% CI 1.094-1.164) or Medicare insurance (OR 1.056; 95% CI 1.021–1.093), and metastasis at time of diagnosis (OR 1.318; 95% CI 1.275–1.361) were associated with Bx diagnosis. Factors associated with an imaging diagnosis were female (OR 0.964; 95% CI 0.941–0.987), Asian/Pacific Islanders (OR 0.686; 95% CI 0.657–0.717), more comorbidities (OR 0.578; 95% CI 0.559–0.597), treatment at an academic center (OR 0.447; 95% CI 0.436–0.458), hyperbilirubinemia (OR 0.807; 95% CI 0.784-0.831) or elevated AFP (OR 0.571; 95% CI 0.549-0.594). Over the examined study period 2004-2015, imaging diagnosis was increasingly used. Conclusions: Although imaging alone can be adequate to diagnose many cases of HCC, nearly half of the cohort underwent a Bx. Even though diagnosis by imaging was more frequently used in recent years, there were still racial and institutional differences in pattern of care.
Dose intensity of nab-paclitaxel and gemcitabine chemotherapy in metastatic pancreatic cancer.
Authors: Lim Alexander , Kim Dae Won , Kim Kunhwa , Kim Richard D. , Bottiglieri Salvatore Michael 
Published: January 2019

251 Background: Combination chemotherapy with nab-paclitaxel/gemcitabine is a standard of care option in metastatic pancreatic cancer management with increasing use due to an improvement in median overall survival of 1.8 months compared to gemcitabine alone. It is also used in practice in the second and third-line settings for patients that have progressed on fluorouracil based regimens. As the utility of this combination chemotherapy has grown, dose intensity (DI) in relation to survival outcome is an important measure for real world application. Methods: Fifty-six patients that were 18 years or older with metastatic pancreatic cancer treated with nab-paclitaxel/gemcitabine as first-line therapy from January 1, 2013 to December 31, 2014 at Moffitt Cancer Center were identified through medical records. The subjects were retrospectively reviewed, and demographic, treatment outcomes (survival and progression), and DI were collected. Overall survival was calculated with Kaplan Meier survival curves. Multi-Cox regression models estimated multivariable-adjusted hazard ratio with 95% confidence intervals. Results: There was no significant relationship between receiving a DI > 85% regimen in relation to independent variables of age > 65, sex, primary site, and known distant metastasis; however DI > 85% was significant for patients that received additional chemotherapy following nab-paclitaxel/gemcitabine (p = 0.044). The DI > 85% group compared to the < 85% group had a hazard ratio (HR) for all-cause mortality of 0.285 (0.106-0.764, p = 0.013). Six and 12-month survival were higher in the DI > 85% group (p = 0.009, p = 0.02 respectively). Conclusions: DI > 85% for nab-paclitaxel/gemcitabine compared to DI < 85% may have a lower all-cause mortality and higher 6 and 12-month survival.
Imaging findings of patients undergoing SBRT for HCC after prior TACE.
Authors: Maleeva Aneliya , Thomas Tarita , Yacoub Joseph H 
Published: January 2019

252 Background: Our purpose is to assess the treatment response using follow up MRI or CT in lesions treated with stereotactic body radiation therapy (SBRT) after transarterial chemoembolization (TACE). Methods: Twenty-six patients treated with liver SBRT at our institution in the period between 2015 and 2017. Of these we included patients who had lesions diagnosed as HCC (LR-5) or probable HCC (LR-4), and who had prior TACE with a residual/recurrent enhancing component on the pre SBRT images with adequate post SBRT imaging. One radiologist (5 year experience) evaluated all pre and post SBRT imaging and measured the lesion size and the size of the largest enhancing component. Lesion decrease or increased in size was assessed based on the mRECIST criteria. Explant pathology results were collected for patients who received transplant. Necrosis > 90% on explant was considered full response to treatment. AFP (alpha-fetoprotien) values before and after SBRT were collected. Results: Eight patients with 9 lesions meet our inclusion criteria, 3 of which were LR-5 and 6 LR-4 prior to the TACE. At 3 month, 2 lesions had no residual enhancing component, 2 lesions decreased in size, 2 lesions increased in size, 3 lesions remain unchanged. After maximum available follow-up (ranging from 3 to 8 months), 3 lesions had no residual enhancing component, 2 decreased, 2 lesions increased in size, 2 lesions remain unchanged. Of the 3 lesions that were definitive HCC (LR-5): 1 lesion decreased in size, 2 lesions increased in size. 4 of 8 patients (4 lesions) underwent transplant, 3 of them showed only 50% necrosis on explant. 1 of 3 lesions showed no change in size by imaging, the other 2 lesions had no residual enhancing component. Only 1 lesion had full response on the transplant. This lesion was unchanged on 3 and 6 months follow up. The AFP was not helpful since the majority of the patient had low pre-treatment AFP. Conclusions: Patient with viable disease on imaging after TACE subsequently treated with SBRT demonstrated variable behavior on imaging. Close to half demonstrated resolution of the enhancing component, however, in the few that had explant follow up there was no correlation between imaging findings and pathology.
Investigation of aberrant DNA methylation in association with cisplatin-resistant hepatoblastoma.
Authors: Fujiyoshi Sunao , Honda Shohei , Hiyama Eiso , Taketomi Akinobu 
Published: January 2019

258 Background: Cisplatin (CDDP) is a key-drug of mainstream treatment for hepatoblastoma (HB), but 22.3% of HB patients have resistance to CDDP, and their prognoses are poor. We investigated methylation status of HB patients and identified CDDP resistant candidate genes in HB. Methods: First, we performed a genome-wide methylation array analysis of 11 resected HB tumors. These cases included six cases of RECIST (Response Evaluation Criteria In Solid Tumors) CR or PR (S group) and five cases of SD or PD (R group). We analyzed methylation status of these patients, comparing with clinical course, and selected significant differentially methylated genes. Next, We made CDDP-resistant HepG2 cells by repeated CDDP treatments for a year, then compared expression levels between the CDDP-resistant cells and original cells, using cDNA microarray analysis. We selected CDDP resistant candidate genes from these data. Results: In methylation array analysis data, unsupervised hierarchical clustering analysis showed that methylation profiles were separable into 2 groups in accord with clinical S group and R group. In principal component analysis, the S group also showed a different methylation pattern to the R group. We compared survival rates using Kaplan-Meier method, and results showed that the R group had poorer prognosis significantly. The R group showed 336 hypermethylated genes and 106 hypomethylated genes around the transcriptional start site compared with S group significantly. And in cDNA microarray analysis, 1271 genes were downregulated and 1571 genes were upregulated significantly in CDDP-resistant cells. From among these genes, we selected 15 suppressor and 8 promoter candidate genes that could be related to CDDP-resistance. Conclusions: We identified methylation status associated with CDDP resistance and poor prognosis, and 23 candidates genes in HB. Further refining might lead us to find out the pathogenesis of chemoresistance or new target of therapies and biomarkers in HB.
Circulating free tumor DNA copy number index (CNI) as a predictor of therapeutic response in pancreatic ductal adenocarcinomas (PDAC).
Authors: Kundranda Madappa N. , Beck Julia , Bergelin Jana , Dragovich Tomislav , Lucente Patricia , Conn Marie , Naraev Boris , Chang John , Urnovitz Howard , Schütz Ekkehard 
Published: January 2019

261 Background: Cell-free tumor DNA (cfDNA) has potential to provide minimally invasive patient specific biomarkers to monitor tumor burden. Tumor-specific copy number instability (CNI) are used to quantify tumor-derived cfDNA in the plasma. We prospectively computed CNI Scores of cfDNA to compare with radiological and Ca 19-9 responses. Methods: In a laboratory blinded, prospective single-institution study, 119 plasma samples from 33 patients (pts) with PDAC were analyzed. Time-points were at baseline (C1), 2nd (C2) and 3rd (C3) cycle of systemic therapy. Tumor cfDNA was measured with a CNI scoring assay that quantifies cfDNA with somatic macro-alterations. CNI Score (CNIs) of 31 was defined as ref. range (97.5 % - control group; N = 135), pts below this threshold were censored. Progression of disease (PD) defined as C3 CNIs > 93 (3-fold threshold) and difference to the baseline > 31 (dispersion of reference population). Mutant KRAS in plasma was measured using ddPCR in a subset 22 pts. Pts with an increase of > 0.06% (critical difference) were classified PD. Radiologic imaging results were compared with CNIs and CA19-9 changes from baseline to C3, respectively. Results: By standard radiological imaging 33 pts were classified as: 14 PR/CR, 10 SD, 9 PD. 27/33 pts (81%) were evaluable by CNIs which ranged from decrease of 2017 - increase of 645. The C3 CNI classifier yielded a sensitivity of 86% for predicting PD and 95% for SD/PR/CR. KRAS classification yielded an accuracy of 72%, and only 3/9 PD were accurately predicted (33%). 26/33 pts were secretors evaluable by CA19-9. Only 2/8 PD pts showed increasing values in CA19-9 and 6/8 of evaluable by CNI; 5/6 showed increasing CNI scores. 3/20 deemed as SD on imaging with increasing values of CA19-9 were noted to have decreasing CNIs. CNI Score classification was significantly better than CA19-9 (P = 0.001 and 0.63, respectively). Conclusions: Our evaluation of a comparative study on cfDNA and CA19-9 versus imaging suggest that CNI quantification is potentially a more reliable blood-based marker for early assessment of efficacy to systemic therapy in PDAC. Furthermore, for patients not expressing CA19-9 it could serve as an alternative monitoring aid.
The impact of the immune microenvironment in patients with GEP-NETs.
Authors: Baretti Marina , Zhu Qingfeng , Zahurak Marianna , Pawlik Timothy M. , Anders Robert A , De Jesus-Acosta Ana 
Published: January 2019

267 Background: The immune microenvironment in neuroendocrine tumors (NETs) remains largely unexplored with very limited data evaluating its impact on survival. We aimed to characterize the immune microenvironment and lymphocytic infiltrate in patients with gastroenteropancreatic (GEP) NET. Methods: We performed comprehensive immune profiling for CD3, CD8, PD-1, IDO, and PD-L1 expression in two cohorts of patients with primary GEP-NET: patients who had short progression free survival (PFS) ≤ 4 years (n = 12) or long PFS > 4 years (n = 14) following surgical resection. Tumor associated immune infiltrates in the tumor, inner and outer invasive front were recorded and quantified. The percentage of PD-L1 membranous expression was manually counted in tumor, stroma and invasive front. To account for the correlation among multiple samples within the same patient, generalized estimating equations (GEE) were used for model estimation and hypothesis testing. Results: Patients with shorter PFS had larger primary tumor size compared to patients with longer PFS (Wilcoxon p value = 0.02), with no statistically significant differences in Ki-67 expression. For all patients univariate GEE results showed a higher mean expression of CD3+, CD8+, and PD-1+ cells at the interface (inner and outer) as compared to the tumor region: 1.28 (95% CI: 0.98, 1.58, p < 0.0001), 0.99 (95% CI: 0.67, 1.32, p = 0.0005) and 1.38 (95% CI: 0.90, 1.38, p < 0.0001) respectively. Comparison between the two groups showed that tumors from patients with a longer PFS had higher intratumoral CD3+ TILs densities than did those from patients who had a shortened PFS (0.88, 95% CI: 0.44, 1.31, p = 0.004). Intratumoral expression of CD8+TILs, and IDO+ cells tended to be higher in the long PFS group (p = 0.143 and 0.29 respectively). While the probability of positive PD-L1 expression did not differ according to location, it was higher in patients with shortened PFS (odds ratio = 1.96; 95% CI: 0.64, 5.93), though not significant. Conclusions: Higher intratumoral T cell infiltrate (CD3+) is associated with a favorable outcome and longer PFS following resection for GEP-NETs. Immune escape is a potential mechanism for disease progression and warrants further investigation as a therapeutic strategy for this disease.
Phase II pharmacokinetics of oral SM-88 in heavily pretreated advanced pancreatic ductal adenocarcinoma (PC).
Authors: Noel Marcus Smith , Fernandez-Zapico Martin , Sokol Gerald H. , Del Priore Giuseppe 
Published: January 2019

277 Background: SM88 is an oral tyrosine isomer ( TI) and repurposed drugs (CYP3a4 inducer, mTOR inhibitor, oxidative stress catalyst). This regimen has reported no drug related grade 3, 4 or 5 adverse events (JCO 2013 31: e22095) and potential clinical activity in PC (JCO 2018 36: TPS 4156). PC patients have risk factors for malabsorption and a cachexia syndrome rendering some oral therapies potential unreliable. We present PK data from the completely enrolled first stage of an ongoing dose finding phase II in PC. Methods: Open label randomized TI (control – 230 mg bid vs. experimental - 430 mg bid) along with the lowest approved doses of the other agents. Samples were drawn from four patients at pre-dose and up to six h post dosing on cycle day one for two cycles after a single dose of all four components. Results: Mean age: 71.3 (59 – 80), BMI = 25.3 (21.9 – 28.8) and median three prior chemo lines, two post-pancreas surgery and one s/p RT. There was no evidence that the combination altered the expected PKs at C2. There were no serious drug related adverse events. Favorable RECIST, PERCIST or biomarker activity was documented at both TI dose levels. The PK results of the repurposed drugs were consistent with the published data for these agents, despite the combination use and lower than typical label doses; data will be provided. These results were consistent with previous animal and healthier patient PK of SM88. Conclusions: Single dose C1 and C2 TI PKs are consistent with preclinical predictions (ESMO 2016. Ann Oncol (2016) 27 (supp_6): 1605P) and those previously reported in a healthier population of cancer patients (JCO 2018 36: TPS 4156). Based on these results and PK ones from the repurposed drugs, additional data is being collected in order to define the ongoing phase II expansion cohort dose. SM-88 appears to have predictable PK even in heavily pretreated PC patient with prior radiotherapy and surgery. Clinical trial information: NCT03512756. [Table: see text]
Ligand-inducible, prostate stem cell antigen (PSCA)-directed GoCAR-T cells in advanced solid tumors: Preliminary results from a dose escalation.
Authors: Becerra Carlos Roberto , Hoof Pamela , Paulson Andrew Scott , Manji Gulam Abbas , Gardner Olivia , Malankar Aditya , Shaw Joanne , Blass Devin , Ballard Brandon , Yi Xiaohui , Anumula Madhavi , Foster Aaron E. , Senesac Joseph , Woodard Paul 
Published: January 2019

283 Background: PSCA, a cell surface protein, is upregulated in many solid tumors and correlates with disease stage. BPX601 is an autologous, T-cell product engineered to contain a PSCA-CD3ζ CAR plus the small molecule rimiducid (Rim)-inducible MyD88/CD40 costimulatory domain. BPX601 is optimized for antigen-directed and independent T cell activation, proliferation and persistence, potentially enhancing efficacy in solid tumors versus traditional CARs. This first-in-human study assesses the safety, biological and clinical activity of BPX601 plus Rim in select PSCA-positive cancers. Methods: NCT02744287 is a two-part, open-label trial. Part 1 is an ongoing 3+3 cell dose escalation to identify the recommended BPX601 cell dose (Day 0) given in combination with a fixed, single Rim dose (0.4 mg/kg; Day 7). Eligibility criteria include previously treated metastatic pancreatic cancer (mPDAC) with measurable disease & positive PSCA expression. Results: Patients received only cyclophosphamide (CTX) for lymphodepletion (LD) within three days before BPX601 infusion. Nine adults have been treated across three cell dose levels (cells/kg): 1.25x106 (cells only), 1.25x106+Rim, 2.5x106+Rim. All had mPDAC with ≥ two prior therapies. Common AEs were fatigue and nausea. No DLTs, related SAEs, neurotoxicity or CRS events were reported. Rapid cell engraftment by Day 4 was observed in all patients. No evidence of LD with CTX was seen. Of six patients that received Rim: two had cell expansion 10- to 20-fold within seven days; two had cell persistence > three weeks; all had elevated serum cytokines (IP-10, TNFα) correlated with cell expansion. Best response after ≥ one scan was 4 SD ≥ eight weeks with two minor responses (not confirmed; one patient had matched CA19-9 decrease) and 2 PD. Disease control without new therapy was 16 and > 11 weeks (ongoing) in one and two patients, respectively. Conclusions: BPX601 with single-dose Rim was well-tolerated and resulted in enhanced T cell expansion and prolonged persistence in some patients despite lack of LD. Evidence of clinical benefit in this heavily pretreated mPDAC population was seen. Part 2 is planned to open soon and will include CTX/fludarabine LD to maximize engraftment as well as gastric and prostate cancers. Clinical trial information: NCT02744287.
MAPK pathway proteins expression and correlation with clinicopathological indices and long-term outcome according to the etiology of underlying chronic liver disease in hepatocellular carcinoma.
Authors: Diniz Paulo Henrique Costa , Silva Serena Dafne do Carmo , Sampaio Caio Cesar Lobo , Vidigal Paula Vieira Teixeira , Xavier Marcelo Antonio Pascoal , Faria Luciana Costa , Ferrari Teresa Cristina de Abreu 
Published: January 2019

286 Background: Different etiologies of chronic liver disease (CLD) potentially lead to hepatocellular carcinoma (HCC) by multiple mechanisms that can be translated into clinicopathological and prognostic differences. We evaluated the expression of some proteins of MAPK pathway, an important signalling cascade in HCC, and correlated them to clinical and histopathological parameters, and long-term outcome, according to the etiology of the CLD. Methods: 80 patients (pts) who underwent orthotoptic liver transplantation (OLT) for HCC at Universidade Federal de Minas Gerais, a referral center in Brazil, were randomly selected: 41 viral (V) (HBV or HCV infection), 39 nonviral (NV) (alcohol abuse and cryptogenic) etiology. Clinical pre-OLT and histological data were retrospectively collected. Event (E) was defined as death and/or HCC-recurrence since OLT. In explanted liver, tumor and adjacent cirrhosis were subjected to immunohistochemistry, using antibodies against K-RAS, B-RAF and MEK, analysed by two pathologists. Results: V and NV groups were well balanced regarding clinicopathologic indices, but alcohol was the main etiology in men (95%) and HCV in women (38.7%). Median E-free survival (EFS) was 74.5 months (range, 8.5-105), without difference between groups. Microvascular invasion (MIV) (p < 0.01) and age (p = 0.04) were independently associated with E. 11 pts (26.8%) of the V group had strong expression (SE) of K-RAS in tumor comparing to 0 (0%) in cirrhosis (p = 0.008) and to three (7.7%) in NV group HCC (p = 0.024). SE of B-RAF was seen in seven pts (17.0%) in V versus 11 (28.2%) in NV (p = 0.257), without difference from cirrhosis (p = 0.755). SE of MEK was not seen. Weak KRAS expression was more common in older pts (p = 0.04). The proteins expression was not related to E or EFS. Conclusions: SE of K-RAS, but not of BRAF and MEK, were more frequent in V group HCC than in cirrhosis and NV group tumors. It suggests that HBV and HCV can lead to HCC by different mechanisms comparing to NV etiology and KRAS could have a role on carcinogenesis. As there were no differences in clinical outcomes, prognostic, and therapeutic implications need to be stablished.