bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of soluble TGF-beta and its dynamics for predicting the prognosis in unresectable pancreatic cancer patients treated with chemotherapy.
Authors: Park Hyunkyung , Bang Ju-Hee , Nam Ah-Rong , Park Ji Eun , Kim Mei Hua , Bang Yung-Jue , Oh Do-Youn 
Published: January 2019

288 Background: Transforming growth factor-beta (TGF-β) is a multifunctional regulatory factor. Here, we measured serum soluble TGF-β (sTGF-β) levels and evaluated its dynamics and prognostic capabilities during chemotherapy in unresectable pancreatic cancer patients. Methods: Sixty patients treated with FOLFIRINOX as the first-line palliative chemotherapy were prospectively enrolled. We prospectively collected blood samples at the time of diagnosis, first response assessment, and disease progression and measured serum sTGF-β using an enzyme-linked immunosorbent assay. Results: The patients’ median overall survival (OS) and progression free survival (PFS) were 10.3 (95% confidence interval [CI], 8.5–12.1) and 6.5 (95% CI, 4.9–8.1) months, respectively. Patients with low sTGF-β at diagnosis ( < 31.2ng/mL) had better OS and PFS than patients with high sTGF-β, respectively (OS, 13.7 vs. 9.2 months; hazard ratio [HR], 2.602; P =0.004; PFS, 9.0 vs. 5.8 months; HR, 2.010; P =0.034). At the time of disease progression, sTGF-β was increased compared with that of diagnosis (mean 26.4 vs. 23.9ng/mL). Especially, in patients with a partial response, sTGF-β was significantly increased at disease progression (mean 25.7 vs. 31.0ng/mL; P =0.049). Conclusions: Pre-treatment sTGF-β levels serve as a prognostic indicator in unresectable pancreatic cancer patients treated with FOLFIRINOX chemotherapy. Likewise, the dynamics of sTGF-β during chemotherapy have prognostic value.
Feasibility and clinical utility of EUS guided biopsy of pancreatic cancer for next-generation genomic sequencing.
Authors: Dreyer Stephan , Jamieson Nigel , Evers Lisa , Jones Marc , Martin Sancha , Duthie Fraser , Musgrove Liz , Cooke Susie , Bailey Peter , McKay Colin , Chang David Kuang-Fu , Biankin Andrew 
Published: January 2019

296 Background: Next-generation sequencing technology has made genomic profiling guided therapy a reality for many cancer types. The aim of this study is to investigate the feasibility of genomic profiling using standard clinical endoscopic ultrasound (EUS) core biopsy samples of Pancreatic Cancer (PC) to allow personalised cancer care. Methods: 78 patients underwent additional research biopsy at the time of diagnostic EUS biopsy. En-face frozen section was performed to enable targeted macro-dissection prior to DNA extraction, quantification and targeted gene sequencing (Agilent Comprehensive Cancer Gene Panel). Matching formalin-fixed (FFPE) diagnostic EUS biopsies and fresh frozen surgical resection specimens also underwent genomic profiling for comparison. Whole genome (WGS) and RNA sequencing was performed in selected patients. Results: Targeted panel sequencing ( n = 61) revealed known PC genes ( KRAS, GNAS, TP53, CDKN2A, SMAD4) in 36 patients with histological evidence of PC. Potentially actionable somatic mutations (BRCA1, BRCA2, ATM, BRAF, JAK3) were found in 6 (17%) patients. WGS ( n = 5) of EUS samples confirmed mutations identified on panel sequencing and revealed relevant mutational signatures and structural variation patterns that can act as putative biomarkers of therapeutic responsiveness. RNA sequencing ( n = 54) segregated patients into key clinically relevant molecular PC subtypes based on transcriptome and reveals novel molecular insights into advanced, unresectable PC ( n = 38). Conclusions: We demonstrate here novel multi-omic analysis of pancreatic cancer using standard clinical EUS guided fine needle biopsies. Multi-omic analysis of EUS biopsies offers potential clinical utility to guide personalized therapy of PC in both the neoadjuvant and advanced settings.
Physical, emotional, and informational challenges of patients living with neuroendocrine tumors in the United States: Understanding their unmet needs.
Authors: Goldstein Grace , Majdi Abdelali , Bocher-Pianka Isabelle , Watts Rupert , Khan Mohid 
Published: January 2019

299 Background: Surveys of neuroendocrine tumor (NET) burden on daily living rarely explore the impact that patient information sources can have on optimizing care. This subset of a large US survey focused on identifying the unmet needs, and available information sources and support that address the physical, emotional and informational challenges that patients with NETs experience. Methods: The Carcinoid Cancer Foundation is a US, non-profit organization that encourages and supports research and education on carcinoid and related NETs. A Carcinoid Cancer Foundation-approved survey was shared with patients with NETs via the Carcinoid Cancer Foundation website, e-newsletters and social media; some patients were emailed direct links to the online survey. Results: US, online surveys (N=428; 13 questions) were completed over 6 weeks in 2015. Patients had mostly small intestinal (40%), lung (13%) or pancreatic (11%) primary tumors; 66% of patients were diagnosed in the previous 5 years. Patients experienced multiple symptoms, most commonly diarrhea (47%), flushing (45%), changes in bowel/bladder habits (37%) and persistent pain (30%). Common emotions upon diagnosis were fear (58%), anxiety (53%), feeling overwhelmed (50%), confusion (39%) and sadness (34%). Greatest physical challenges were fatigue (66%), diarrhea (48%), pain/discomfort (40%) & sleep disturbance (35%). “Very useful” information sources were (1) NET/carcinoid disease awareness website, (2) carcinoid/NET support group, (3) Google, (4) discussion forums and (5) governmental/health-authority websites. Favored information formats included “patients-like-me” case studies (67%), email (59%), e-newsletters (56%), FAQs (50%), short interactive tutorials (32%) and “top tips” (31%). Information sought, but not found, included simple advice on diet, holistic treatment, complementary therapies, where to find the best treatment, pain management & prognosis. Conclusions: In the US, patients with NETs face negative emotions and multiple physical challenges that require psychological support/coping strategies, and they seek reliable, personally relevant, easily understood information, including that from interaction with other patients.
Impact of lung and heart dose on survival after radiotherapy for esophageal cancer.
Authors: Oh Patrick , Zhang Minsi , Brady Paul , Yorke Ellen , Won Elizabeth , Goodman Karyn A. , Wu Abraham Jing-Ching 
Published: January 2019

3 Background: Chemoradiation is an essential tool in treatment of localized esophageal cancer. Recent data indicates that cardiac dose is an independent predictor of survival after chemoradiation for locally advanced lung cancer. However, the impact of normal tissue dose in esophageal cancer has not been well characterized. We investigated cardiac and pulmonary dose-volume histogram (DVH) metrics as potential predictors of overall survival (OS) after chemoradiation for esophageal cancer. Methods: We reviewed 453 consecutive patients with stage I-III esophageal cancer treated with definitive or preoperative chemoradiation (median dose 50.4 Gy in 28 fractions) between 2007 and 2015 at our center. Most (n = 442) received intensity-modulated radiation therapy. Radiation plans were reviewed and multiple DVH metrics for heart (max and mean dose, V5Gy, V10Gy, V20Gy, V30Gy, and V40Gy) and lung (mean dose, V5Gy, and V20Gy) were extracted for analysis. Other clinical covariates (surgery, performance status, stage, and histology) were recorded. Cox univariate (UVA) and multivariate (MVA) regression was used to analyze the association of these factors with overall survival. Results: Median follow-up for surviving patients was 28.4 months. On UVA, older age, lower performance status, Stage III disease, lack of surgery, heart V40Gy, lung V5Gy, lung V20Gy, and lung mean dose were significantly associated with decreased survival. On MVA, surgery (p = 0.008), stage III disease (p < 0.0002) and lung V20Gy (p = 0.0389) remained significant, while heart V40Gy did not (p = 0.211). Patients with lung V20Gy< 20% had a median survival of 44.0 months, compared to 24.0 months for patients with lung V20Gy≥20%. Conclusions: This comprehensive dosimetric analysis of heart and lung dose in a large cohort of esophageal cancer patients suggests that lung dose is a significant independent predictor of survival. Cardiac dose was not independently predictive after adjusting for lung dose and other clinical factors. This data suggests that esophageal cancer outcomes may be improved by minimizing lung dose, particularly the volume receiving 20Gy or more, and provides further rationale for pursuing new techniques to reduce lung dose, such as proton therapy.
A novel morphologic and metabolic feature fused treatment response evaluation pipeline for pancreatic adenocarcinoma patients.
Authors: Lao Yi , David John , Torosian Arman , Yang Wensha , Tuli Richard 
Published: January 2019

311 Background: Adaptive radiation therapy for pancreatic adenocarcinoma (PA) relies on accurate treatment response assessment. Traditional RECIST criteria poorly characterize tumors with complex morphological features, while PET imaging inefficiently detects tumors with intrinsically low standardized uptake value (SUV). Here, we performed regional comparisons of 3D intact PA surfaces pre and post chemoradiotherapy (CRT) utilizing surface measurements containing both morphological and metabolic features to better assess response. Methods: Twenty-one locally advanced PA patients with pre- and 6-8 week post-CRT 18F FDG-PET/CT scans were evaluated. Boundaries of initial and post-CRT tumors were manually defined on respective CT images. On each of the tumors, 3D meshes were generated, followed by surface based registration to achieve vertex-wise correspondence. For each surface vertex, a multivariate vector was formed from two components: anatomic (deformation tensors resulted from surface registration), and metabolic (regional SUV obtained from radius to surface projections). To assess tumor response, paired mahabanobis distance (Mdist) between pre- and post-CRT tumor surfaces with previously formed multivariate vectors were calculated for each patient. Mdist was evaluated using Cox analysis correlated with overall survival (OS) and compared with measurements based on serum CA19-9, volume, SUVmax and SUVmean. Results: Among all the tested parameters, Mdist is the best predictor of OS, with a hazard ratio of 0.437 (p = 0.036). Post-CRT versus pre-CRT ratios based on volume and SUVmax both reached borderline significance (p = 0.0769 and 0.0799, respectively), while CA19-9 and SUVmean failed in predicting OS in our small cohort of patients. Conclusions: We introduced a PET/CT-based novel morphologic and metabolic pipeline for post-CRT response evaluation in locally advanced PA. The fused Mdist outperformed traditional morphologic, metabolic, and physiological measurements in OS prediction. The presented fused model may serve as a new biomarker to better characterize the heterogeneity of tumor response to CRT and a predictive marker for surgical resection.
Genetic heterogeneity of primary lesion and metastasis in small intestine neuroendocrine tumors.
Authors: Walter Dirk , Harter Patrick , Battke Florian , Winkelmann Ria , Schneider Markus , Holzer Katharina , Koch Christine , Bojunga Jörg , Zeuzem Stefan , Hansmann Martin-Leo , Peveling-Oberhag Jan , Waidmann Oliver 
Published: January 2019

312 Background: Data on intratumoral heterogeneity of small intestine neuroendocrine tumors (SI-NETs) and related liver metastasis is limited. Further investigation might have impact on development of targeted therapy regimens. The aim of the study was to characterize genetic heterogeneity of 5 patients suffering from SI-NETs. Methods: Formalin-fixed, paraffin-embedded tissues samples of primary and metastatic lesion as well as benign liver of five patients with synchronously metastasized, well or moderately differentiated SI-NETs were analyzed with whole exome sequencing. For one patient, chip based 850k whole DNA methylome analysis was performed of primary and metastatic tumor tissue as well as control tissue. Alterations that occurred only in one tumor site were defined as private, whereas mutations present in both metastasis and primary lesion were regarded as common. Results: 156 single nucleotide variants (SNVs) in 150 genes were identified and amount of mutations/per sample ranged from 9-34 (mean 22). The degree of common (0-94%) and private mutations/per sample was strongly varying (6-100%). In all patients, copy number variations (CNV) were found and the degree of intratumoral heterogeneity of CNVs corresponded to SNV analysis. DNA methylation analysis of a patient without common SNVs revealed are large overlap of common methylated CpG sites. Conclusions: SI-NET primary and metastatic lesions show a highly varying degree of intratumoral heterogeneity. Driver events might not be detectable with exome analysis.
A phase I study of veliparib (Vel) in combination with oxaliplatin (Ox) and capecitabine (Cap) in advanced solid tumors.
Authors: Turk Anita Ahmed , Deming Dustin A. , Lubner Sam Joseph , Mulkerin Daniel , LoConte Noelle K. , Tevaarwerk Amye , Wisinski Kari Braun , Eickhoff Jens C. , Liu Glenn 
Published: January 2019

314 Background: Poly(ADP-ribose) polymerases (PARP) are activated by DNA strand breaks and important for DNA repair in response to platinum-based chemotherapy. PARP inhibition with Vel might enhance anti-tumor effects of Cap with Ox. This phase I study (NCI 8604) examines the tolerability, safety and preliminary efficacy of the combination of Vel with Cap and Ox. Methods: This is a phase I dose escalation protocol testing escalating doses of Vel with Cap and Ox every 28 days (Table 1). Pts were treated in cohorts of 3-6 pts until cycle 1 DLTs were defined. Key eligibility criteria included age ≥ 18 with histologically confirmed malignancy meeting at least one of the following: documented BRCA1/2 mutation and a BRCA related malignancy; a 20% probability of harboring a BRCA mutation; metastatic colorectal cancer; mucinous ovarian cancer; other GI malignancy in which Ox has demonstrated activity. Results: 17 pts (median age 52 [range 19-71]; 14 female, 3 male) were treated at 4 dose levels (DL) (Table 1). Pts had cholangiocarcinoma (6), breast (4), ovarian (4), neuroendocrine (1), pancreas (1), and colon (1) cancers. 7 pts (4 breast, 3 ovarian) are BRCA1+. Dose escalation was initiated at DL1. One DLT (mucositis) occurred at this dose level. At DL2, two DLTs (mucositis with neutropenic fever and thrombocytopenia) were noted. The protocol was amended for escalation to begin at DL1A. At DL2A, a grade 2 DLT of fatigue requiring dose delay occurred in one pt. Pts were on study for median 10 weeks (range 1 – 88). 24% of pts remained on study ≥ 6 months. Of the 14 pts with measurable disease, 5 had PR (2 ovarian, 2 breast, 1 colon) and 4 had SD (3 cholangiocarcinoma, 1 pancreas). Common AEs include nausea/vomiting (94%), diarrhea (47%), mucositis (41%), anemia (35%), neutropenia (24%), and thrombocytopenia (18%). Conclusions: Vel in combination with Cap and Ox is safe and well tolerated in pts with advanced solid malignancies. The recommended phase II dose is DL2A Vel 40mg BID (D 1-7, 15-21), Cap 1000mg/m2 BID (D 1-7, 15-21), and Ox 85mg/m2 (D 1 and 15). Clinical trial information: NCT01233505. [Table: see text]
Pilot evaluation of PD-1 inhibition in metastatic cancer patients with liver transplantations (LT): The Mayo Clinic experience.
Authors: DeLeon Thomas , Salomao Marcela , Aqel Bashar A. , Sonbol Mohamad B. , Bryce Alan Haruo , Borad Mitesh J. 
Published: January 2019

328 Background: Patients with a history of solid organ transplants have been excluded from PD-1/PD-L1 inhibitor clinical trials due to concern for graft rejection. Only 2 case reports of PD-1 inhibitor use in patients with liver transplantation (LT) have been reported thus far. Here, we report our experience with using checkpoint inhibitors in metastatic cancer patients with LT. Methods: A single center pilot evaluation was conducted to evaluate the safety and efficacy of PD-1/PD-L1 inhibitors in patients with LT. PD-L1 staining on both the tumor and allograft were assessed if there was available tissue. The primary endpoint was evaluation of the risk for allograft rejection. Secondary endpoints included RECIST v1.1 and Immune-Related Response criteria (iRC) response rates, progression free survival (PFS) and overall survival (OS). Translational objectives included the relationship of PD-L1/PD-1 staining of tumor/allograft with response and rejection. Results: Six metastatic cancer patients with a history of LT received PD-1 inhibitor therapy (hepatocellular n=5, melanoma n=1). 3 patients were on mTOR inhibitor as immunosuppressive regimen and 3 on calcineurin inhibitor. Overall, allograft rejection was observed in 1/6 patients (on mTOR inhibitor). One patient achieved a CR (melanoma), 3 patients had PD and 2 patients discontinued therapy prior to restaging assessments. A single response (by both RECIST v1.1 and iRC) and rejection were reported in patients who received mTOR inhibitors (1 of 3). Three patients were tested for PD-L1 staining in the allograft tissue and all of them were negative (0% staining) with no graft rejections observed. Four patients had tumor PD-L1 evaluated (2 patients tested positive with 1 patient obtained a CR). The median OS, PFS and duration of therapy were 1.2, 1.8 and 1.2 months respectively. Conclusions: In this pilot evaluation of PD-1/PD-L1 inhibitors in LT patients both preliminary efficacy (1 of 4) and allograft rejection (1 of 6) was exhibited. Larger, prospective trials are needed to elucidate optimal patient and immunosuppressive regimen selection in these patients.
Clinical impact of tumour-infiltrating B-cells in periampullary adenocarcinoma in relation to adjuvant chemotherapy.
Authors: Lundgren Sebastian , Fristedt Richard , Elebro Jacob , Karnevi Emelie , Nodin Bjorn , Warfvinge Carl Fredrik , Micke Patrick , Eberhard Jakob , Tingstedt Bobby , Jirstrom Karin 
Published: January 2019

330 Background: The prognostic significance of tumour-infiltrating lymphocytes of the B lineage in solid cancers has only recently begun to receive attention. Herein, we explored the relationship between B cell and plasma cell density and survival in patients with periampullary adenocarcinoma, including pancreatic cancer, with particular reference to morphological type. Methods: Immunohistochemistry was applied to quantify the abundance of B cells (CD20+), and plasma cells (CD138+) in tissue microarrays with tumours from a retrospective consecutive cohort of 175 patients who had undergone pancreaticoduodenectomy for periampullary adenocarcinoma. Cox regression was applied to calculate univariable and multivariable hazard ratios (HR) for recurrence and death within five years up until March 2017. Multivariable HRs were adjusted for established clinical parameters. Results: High CD20+ cell density was an independent prognostic factor for a prolonged overall survival in both intestinal-type (HR 0.32; 95% CI 0.12-0.86) and pancreatobiliary-type (HR 0.38; 95% CI 0.23-0.66) tumours. CD138+ was an independent prognostic factor in pancreatobiliary-type tumours (HR 0.51; 95% CI 0.32-0.82) only. A significant positive interaction was seen between adjuvant chemotherapy and CD20+ cells in relation to OS for PB-type tumours (pinteraction= 0.027). Conclusions: These results demonstrate that dense infiltration into the tumour by cells of the B lymphocyte lineage confers an improved prognosis in periampullary adenocarcinoma including pancreatic cancer. The impact of B cells in the local anti-tumour response is gradually being unravelled, and their potential influence on adjuvant chemotherapy response in the more aggressive pancreatobiliary-type tumours may be clinically relevant and merits further study.
Effect of conventional liver irradiation on the pharmacokinetics of sorafenib through p-glycoprotein: Results of concurrent and sequential strategy.
Authors: Hsieh Chen-Hsi , Tsai Tung-Hu , Chen Yu-Jen , Wang Li-Ying 
Published: January 2019

338 Background: Sorafenib is a multi-kinase inhibitor that demonstrated a significant improved survival of patients with hepatocellular carcinoma (HCC). The efficacy of radiotherapy (RT) concurrent or sequential with sorafenib in unresectable HCC patients has better effects than single agent. However, the mechanism for local RT on sorafenib in the plasma system remains unclear. Here, we evaluate the mechanism of liver irradiation on the pharmacokinetics (PK) of sorafenib using rats as an experimental model. Methods: Free-moving rat model was used in the current study. Image-guided RT with 2 Gy was delivered to the whole liver of Sprague-Dawley rats. The experimental animals were randomized to (A) the sorafenib-only (40 mg/kg, p.o.) group and (B) pre-treated with cyclosporin A [CsA, p-glycoprotein (p-gp) inhibitor, 20mg/kg, i.p. 30 min before RT] group. In each group, the experimental animals were randomized to sham RT (0 Gy with sorafnib), concurrent (after RT 1 hour) and sequential group (after RT 24 hour), respectively. The PK of sorafenib in the plasma system was calculated. Each group’s data was collected from six rats Results: For sorafenib-only group, compared to the sham-irradiated controls, the area under the concentration versus time curve (AUC) of sorafenib was increased by 132% in concurrent group [719 versus (vs.) 1669 min*ug/mL, p = 0.046]. On the contrary, the AUC of sorafenib was decreased by 59% in sequential group (719 vs. 297 min*ug/mL, p = 0.036). Compared to the sorafenib-only group, the AUC of sorafenib in the concurrent group pre-treated with CsA was decreased by 83% (1669 vs. 278 min*ug/mL, p = 0.011). Interestingly, the AUC of sorafenib in the sequential group pre-treated with CsA was increased by 275% (297 vs. 1113 min*ug/mL, p = 0.023). Conclusions: P-pg plays an important role for the PK of sorafenib that was modulated by whole liver irradiation in rodent model. The strategy for modulating the RT-PK phenomenon of sorafenib through p-gp is worth to investigate in the future.