bluuebunny/crossref_metadata_2025_split huggingface dataset:
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 J , Chang David Kuang-Fu , Biankin Andrew 
Published: September 2018

e15755 Background: Next-generation sequencing (NGS) has made genomic profiling to guide 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:Patients undergoing EUS and biopsy for suspicion of PC underwent additional biopsies which was snap frozen. En-face frozen section enabled targeted macro-dissection prior to DNA extraction, quantification and targeted sequencing using a commercially available 151 gene ClearSeq Comprehensive Cancer Panel. Matching formalin-fixed (FFPE) diagnostic EUS biopsy and fresh frozen surgical resection specimens underwent genomic profiling for comparison. Whole genome sequencing (WGS) was performed in 2 patients. RNA sequencing was performed in samples with sufficient RNA yield. Results: Known PC genes ( KRAS, GNAS, TP53, CDKN2A, SMAD4) were identified in 27 out of 30 (90%) patients with histological diagnosis of PC. Potentially actionable somatic mutations (BRCA1, BRCA2, ATM, BRAF, JAK3) were found in 6 (20%) patients. In the 2 samples selected, WGS of the EUS samples confirmed point mutations identified on panel sequencing and revealed relevant mutational signatures and structural variation patterns. Targeted panel sequencing was successful in all FFPE samples. In 1 chemotherapy naïve patient, sequencing of a matching trio of fresh frozen and FFPE EUS biopsies, and resection sample revealed evidence of spatial intra-tumoral heterogeneity. In another patient, pre-treatment biopsy revealed a somatic BRCA1 mutation, and patient had a near complete pathological response to platinum containing neoadjuvant therapy in the resected specimen. RNA sequencing segregated patients into key clinically relevant molecular PC subtypes based on transcriptome as recently described. 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 the neoadjuvant and advanced settings.
Efficacy of alternating-week fixed dose rate gemcitabine (FDR gem) plus capecitabine (CAP) in advanced pancreatic cancer (APC).
Authors: Johns Claire , Diaz Celso L. , Kerridge William , Hwang Jimmy , Ko Andrew H. , Tempero Margaret A. 
Published: September 2018

e15758 Background: Phase III trials support the use of FOLFIRINOX and gemcitabine plus albumin-bound paclitaxel as first-line treatment options in patients with APC. However, these treatments have significant side effects including cumulative neuropathy and cytopenias that limit their use. Our group previously reported results from a phase II trial evaluating a regimen of alternating-week FDR GEM/CAP showing promising efficacy as well as good tolerability. In the current analysis, we examined a larger retrospective cohort of APC patients treated using this strategy. Methods: Eligible patients received FDR GEM (1000 mg/m2) infusion on days 1 and 15, along with CAP 1,000 mg/m2 on days 1 to 7 and 15-22, in 28-day cycles. We evaluated OS, PFS, and objective radiologic response (ORR) by RECIST 1.1; as well as tabulated adverse events that necessitated dose or schedule modification. Results: 62 patients were treated at UCSF from 2008-2016 (52% male; and 48% female with a median age of 64.3 years. 49 had metastatic disease and 13 were locally advanced. Median OS was 10.3 and 12.0 months in the metastatic and locally advanced cohorts, respectively; median PFS was 5.4 and 5.6 months. ORR in evaluable patients with metastatic disease was 19% (all partial responses), with a disease control rate of 64%. In total, 37% of patients required dose modification at some point during therapy; the most common reason was hand-foot syndrome. Conclusions: FDR GEM/CAP represents an active and safe regimen for patients with APC, with OS and PFS rates comparable to those achieved with other first-line treatments. This regimen, based on its ease of administration and tolerability, may represent a suitable alternative option in select patients.
Effect of Rho/ROCK pathway inhibition on metastasis-free and overall survival in biomarker selected, orthotopic, patient-derived models of pancreatic cancer.
Authors: Chin Venessa T. , Nagrial Adnan , Conway James , Vennin Claire , Chantrill Lorraine A. , Chou Angela , Steinmann Angela , Gill Anthony J. , Humprhis Jeremy , Drury Alison , Froio Danielle , Morgan Ashleigh , Biankin Andrew , Timpson Paul , Pajic Marina 
Published: September 2018

e15759 Background: PC is a highly lethal disease which metastasises early. The sequencing efforts of the Australian Pancreatic Cancer Genome Initiative (APGI) identified ROCK-1 as a target of interest. The Rho/ROCK pathway is essential in cellular movement, metastasis, vasculogenesis and stromal signaling. Fasudil (F) is a ROCK inhibitor which has been shown to be safe for human use. Using unique, patient derived models, we have previously shown that F plus gemcitabine (G) does not reduce cellular proliferation in vitro but reduces tumour size and improves overall survival (OS) in subcutaneous patient-derived xenografts (PDX). However, PDXs are critisised for not fully recapitulating the human condition. Here we aimed to generate a patient-derived orthotopic xenograft (O-PDX) which could be used to assess the effects of F + G on metastasis formation and OS. Methods: One patient-derived cell line (PDCL) was labled with firefly luciferase. This was injected into the pancreas of NOD/Shi- scid/IL-2Rγnull (NSG) mice to generate the O-PDX model. The O-PDX was imaged weekly with the IVIS imaging system. The O-PDXs were treated with saline control (S) (n = 8), gemcitabine (G) (n = 10) fasudil (F) (n = 6) or gemcitabine + fasudil (GF) (n = 10). Mice were culled once radiographic or clinical evidence of ascites was detected. Metastasis free (MFS) and OS were recorded. Vessel quantification was performed via CD-31 staining. Results: Metastases seen (spleen, liver, lung, ovary) on imaging were confirmed using GFP stains on immunohistochemistry. F prolonged MFS but not OS when compared with S. GF significantly prolonged MFS (33.5 versus 43 days; p = 0.0339) and OS (51.5 versus 64 days; p = 0.0035). CD-31 staining showed that treatment with F resulted in increased vascularity in the liver metastases and normal liver tissue but not in the pancreas tumour. Conclusions: The addition of Fasudil to gemcitabine improves MFS and OS in an orthotopic model of PC and is a promising new therapeutic option. The increase in vascularity of the metastases and normal liver tissue suggest that changes in vascularity are important and may result in improved delivery of gemcitabine.
Clinical study of nab-paclitaxel in combination with S-1 as first-line therapy in patients with advanced pancreatic cancer.
Authors: Hu Yi , Sun Danyang 
Published: September 2018

e15765 Background: Pancreatic cancer is one of the highest cancer-mortality diseases worldwide with limited treatment. Most patients had local advanced or metastatic disease at the time of diagnosis. Gemcitabine-based therapy has been standard regimen in the past few decades. It is necessary to find new strategies of treatment. Methods: The aim of this study was to evaluate the efficacy and safety of nab-paclitaxel in combination with S-1 as first-line therapy in advanced pancreatic cancer. We retrospectively evaluated 79 patients with advanced pancreatic cancer from 2014 to 2016 treated in our medical center. All the patients received at least two cycles of combination therapy. Nab-paclitaxel was administered 260mg/ m2 as a total dose on day 1 and 5 or on day 1 and 8. S-1 was administered orally twice a day for 14 days according to body surface area. S-1 monotherapy was administered as maintenance treatment after 6 to 8 cycles of combination therapy until the progression of disease. Results: In all the 79 patients enrolled, the median age was 56, range from 36 to 77, 56 (70.9%) patients had KPS 90, 58 (73.4%) patients had multiple metastatic sites. The overall response rate was 51.9%; median progression-free survival was 5.7 months (95%CI 5.010-6.292); median overall survival was 11.9 months (95%CI 9.731-13.990). The efficacy of CA19-9 decrease > 50% was significant higher compared with those of CA19-9 decrease < 50%. Treatment was well tolerated. Grade 4 toxicity was only reported in neutropenia of 5 patients. Grade 3 adverse events include neutropenia in patients (13.9%), nausea and vomiting in one patient (1.3%), peripheral sensory in one patient (1.3%) and alopecia in 3 patients (3.8%). Conclusions: Nab-paclitaxel in combination with S-1 as first-line therapy demonstrated promising antitumor activity and well-tolerated toxicities and presents a new alternative for locally advanced and metastatic pancreatic cancer.
Prognostic value of positron emission tomography and preoperative CA19-9 in patients treated on a prospective phase II trial of neoadjuvant therapy and surgery.
Authors: Barnes Chad , Aldakkak Mohammed , Christians Kathleen K. , Tolat Parag , Ritch Paul S. , George Ben , Hall William Adrian , Erickson Beth , Evans Douglas B. , Tsai Susan 
Published: September 2018

e15766 Background: The role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging of pancreatic cancer (PC) has not been well defined. We evaluated the prognostic value of FDG-PET imaging in patients with localized PC enrolled in a prospective trial of personalized molecular-directed neoadjuvant therapy. Methods: Pretreatment FDG-PET was classified as high or low based on a standardized uptake value (SUV) cutpoint of 7.2 (population median). Carbohydrate antigen 19-9 (CA19-9) was measured after the completion of neoadjuvant therapy (preoperative) and classified as normal (≤35 U/mL) or elevated. Results: Pretreatment FDG-PET imaging was performed on 100 consecutive patients; SUV was high in 50 and low in 50. Preoperative CA19-9 values were available in 99 of 100 patients; 54 (55%) were elevated and 45 (45%) were normal. Of the 100 patients, 81 completed neoadjuvant therapy and surgery, and 19 were not resected. Among the 81 resected patients, SUV was high in 37 (46%) and low in 44 (54%); preoperative CA19-9 was elevated in 40 (49%) and normal in 41 (51%). The median overall survival (OS) for all patients was 39 months; 45 months for who completed all intended neoadjuvant therapy and surgery and 9 months for patients who were not resected. The median OS for patients with normal CA19-9/low SUV, normal CA19-9/high SUV, elevated CA19-9/low SUV, and elevated CA19-9/high SUV were not reached, 35, 24, and 18 months, respectively (p = 0.0001). Conclusions: Pretreatment FDG-PET avidity and preoperative CA19-9 are important prognostic markers and may be used to estimate the anticipated benefit of surgery; information of immediate clinical significance for both treatment sequencing and the application of surgery to patients who are frequently of advanced age or high-risk.
Extended neoadjuvant chemotherapy (CT) in borderline resectable pancreatic cancer (BRPC): Updated results.
Authors: Kanji Zaheer S. , Rocha Flavio G , Edwards Alicia M , Mandelson Margaret T. , Lin Bruce S. , Kozarek Richard A. , Rose J. Bart B. , Biehl Thomas R , Alseidi Adnan , Helton Scott , Picozzi Vincent J. 
Published: September 2018

e15771 Background: Optimum therapy (Rx) for BRPC is unknown. Since 2008, we have used neoadjuvant Rx with extended course chemotherapy (CT) but not routine neoadjuvant chemoradiation (CRT). Initial results were presented in 2013 (Rose et.al. J Clin Oncolabstr 4043). We present updated findings here. Methods: Patients (pts) were prospectively identified in our institutional PC database. Inclusion criteria: 1) bx-proven PC; 2) radiographic staging per AHPBA/NCCN criteria; 3) no prior Rx; 4) negative staging laparoscopy whenever feasible; 5) all neoadjuvant Rx at our institution, 6) followup ≥ 24 weeks (wks) from initial Rx . Unless disease progression or Rx intolerance noted, pts received gemcitabine/docetaxel (G/D) as neoadjuvant CT x 24 weeks . At that time, all pts felt likely to achieve R0 resection offered surgery; other pts offered 5FU –based CRT if medically fit. Results evaluated by "intent to treat". Results: Among 129 pts, characteristics include median age 66 yrs (range 33-88 yrs), ECOG PS 0/1/2+ 86/36/7, 97%/43% venous /arterial involvement. 78% (101/129) pts completed ≥80% intended CT; 38% (6/16) pts age > 80 and /or ECOG 2+ (p < 0.01) 51% (66/129) pts were resected (44 R0, 22 R1 ≤ 1 mm margin ). 49% (63/129) pts were not (24 disease progression, 17 surgeon decision (anatomy/safety), 11 Rx toxicity/ comorbidity, 6 unresectable at surgery, 5 pt withdrawal). 45% (31/66) and 23% (16/66) resected pts received postop CRT/CT respectively. Median f/u is 47 months (mo). 58% (38/66) resected pts recurred: 18% (12/66) local, 41% (27/66) systemic. For resected pts, median PFS is 25.0 (95% CI: 16.2-32.7) mo, median OS is 37.6 (95% CI: 27.4-58.5) mo. 5-yr OS is 28% ( 95% CI :14-44%). Median OS for non-resected pts is 13.1 (95% CI 10.9-16.9) mo .Median OS for all pts is 22.1 (95% CI: 18.7-28.4) mo. Conclusions: 1.Our series is distinctive with respect to size, use of laparoscopic staging and neoadjuvant G/D CT as standards,and median f/u 2. Pt selection is key; e.g.approach suboptimal for pts > 80 yrs/ ECOG PS 2+ 3. Reported OS compares favorably with other BRPC and de novo resectable PC cooperative group results 4. Detailed analysis of our study (e.g. prognostic factors) will aid future clinical research in BRPC.
Prospective genomic/transcriptomic profiling of advanced pancreatic ductal adenocarcinoma (PDAC) for personalized therapy: Feasibility and preliminary results from the COMPASS study (NCT02750657).
Authors: Aung Kyaw Lwin , Fischer Sandra , Denroche Rob , Jang Gun Ho , Dodd Anna , Creighton Sean , Chadwick Dianne , Timms Lee , O'Kane Grainne M. , Albaba Hamzeh , Southwood Bernadette M. , Ghai Sangeet , Moore Malcolm J. , Miller Jessica , Notta Faiyaz , Wilson Julie , Hedley David W. , Dhani Neesha C. , Gallinger Steven , Knox Jennifer J. 
Published: September 2018

e15776 Background: Prospective characterization of advanced PDAC using whole genome sequencing (WGS) and whole transcriptome sequencing (WTS) may identify patients (pts) who will benefit from a personalized treatment strategy. The feasibility of this approach has not previously been established in PDAC. Methods: Advanced PDAC pts with ECOG PS 0-1 and accessible metastatic or primary tumors, were recruited. A fresh tumor sample for WGS and WTS was obtained by percutaneous biopsy and a reference whole blood sample for germline DNA analysis collected before starting 1st line palliative chemotherapy. Tumor biospecimens were enriched by laser capture microdissection before genomic analysis. The primary endpoint was feasibility (to report WGS results within 56 days in 40 of the first 50 recruited pts.) with a plan to accrue 200 pts. Results: From Dec 2015 – Jan 2017, 42 pts with advanced PDAC safely underwent tumor biopsy (32 liver, 1 omentum, 1 adrenal, 8 primary tumor). Adequate tumor biospecimens were obtained in all but one pt. The median number of tissue cores was 5 (range 3-6). The median post-enrichment tumor cellularity was 77% (range 37-93). WGS was successful for all samples analyzed. In 41 of 42 pts (97.6%), WGS was feasible and results were reported within 56 days (Median 37 days; range 19 to 52 days) meeting the primary endpoint. Potentially actionable somatic genetic aberrations were found in 12 pts (29%) involving ARID1A (N = 4), PIK3CA (N = 1), PDGFRB (N = 1), ERBB4 (N = 1), ATM (N = 2), CDK4 (N = 1) and CDK6 (N = 2). One pt with a germline BRCA2 mutation and another with somatic DSBR mutation signature achieved partial response with FOLFIRINOX (FFX). WTS results were available for 35 pts (85%). Of those, 19 were evaluable for FFX response. Eight of 9 pts (88%) with ‘classic’ signature and 4 of 10 pts (40%) with ‘basal like’ signature had tumor shrinkage with FFX (P = 0.08). Conclusions: Prospective comprehensive genomic profiling of advanced PDAC is feasible with an acceptable turnaround time. Approximately 30% of advanced PDAC pts have targetable genomic signatures and aberrations. RNA signature may predict FFX response.
Updated results of a phase II study of gemcitabine, erlotinib, and S-1 in patients with advanced pancreatic cancer.
Authors: Han Boram , Kim Hyeong Su , Choi Dae Ro , Shim Byoung Yong , Lee Kyung Hee , Kim Jin Won , Kim Jung Han , Kim Jung Hoon , Kim Ho Young , Song Hunho , Park Choong Kee , Moon Sung Hoon , Kim Jong Hyeok , Jeon Jang Yong , Lee Jung Woo , Zang Dae Young 
Published: September 2018

e15778 Background: Gemcitabine-based chemotherapy is considered as a standard front-line treatment for patients with advanced pancreatic cancer. Although addition of erlotinib or S-1 to gemcitabine has yielded better outcomes, it has showed just modest improvement in survival. To overcome this limitation, we evaluated the efficacy and safety of the combination of gemcitabine, erlotinib, and S-1 for the treatment of advanced pancreatic cancer. Methods: Chemotherapy-naïve patients with pathologically proven locally advanced, recurrent or metastatic pancreatic adenocarcinoma were assessed for eligibility. Gemcitabine at 1,000 mg/m2 was administered intravenously on day 1, and 8, erlotinib at 100 mg/day was administered on days 1-21, and S-1 at 60 mg/m2 was administered on days 1-14 every 21 days and continued to maximum of 8 cycles of treatment. Dose escalation of S-1 to 80 mg/m2was permitted from second cycle for pre-defined tolerable patients. Results: Thirty-seven patients (median age 61.5 years) were enrolled. A total of 140 cycles of chemotherapy were administered (median of 3.8; range 1–8 cycles). Toxicities were evaluated in 36 patients, and the responses were evaluated in 32 patients. Major grade 3/4 toxicities included neutropenia (25%), febrile neutropenia (2.8%), fatigue (22.2%), infection (8.3%), vomiting (5.6%), and mucositis (5.6%). The overall response rate was 12.5% [95% confidence interval (CI), 5.1-28.9%] and disease control rate was 71.9% (95% CI, 56.8-86.3%). The median progression-free survival and overall survival were 3.7 months (95% CI, 2.8-4.6 months) and 6.7 months (95% CI, 3.4-9.9 months), respectively. Conclusions: The combination of gemcitabine, erlotinib, and S-1 provided an acceptable toxicity profile and modest clinical benefits in patients with advanced pancreatic cancer. Clinical trial information: NCT01693419.
Nab-paclitaxel plus S-1 as first-line treatment in patients with advanced pancreatic adenocarcinoma.
Authors: Shi Yan , Yan Huan , Han Quanli , Nie Yongkang , Lv Yao , Wang Zhikuan , Dai Guanghai 
Published: September 2018

e15788 Background: Nab-paclitaxel plus gemcitabine and FOLFIRINOX showed survival advantage comparing to gemcitabine monotherapy in metastatic pancreatic cancer (PAC). However, the objective response rates (ORR) were about 30% and still unmet clinical expectation. S-1 is an oral fluoropyrimidine derivative showed comparable and superior clinical benefit in treatment of unresectable and postoperative PAC comparing to gemcitabine. Since nab-paclitaxel and S-1 provided additional clinical benefits in PAC, we conducted a single-arm, phase II trial to investigate the efficacy and safety of nab-paclitaxel plus S-1 as first-line treatment in patients with locally advanced and metastatic PAC. Methods: Nab-paclitaxel was given at 120 mg/m2 intravenously on day 1 and 8, in combination with S-1 which was orally administered (80-120 mg/d according to the body surface area) on day 1-14 of each 21-day cycle, for 6 cycles. The primary endpoint was ORR, secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results: Sixty patients including 5 locally advanced and 55 metastatic PAC received a median of 4 cycles (range from 2 to 6). The ORR by either blinded independent review or investigator assessment was 50.0% (Table). Median PFS and OS were 5.7 months (95%CI, 4.9 to 6.6 m) and 9.3 months (95%CI, 8.3 to 10.3 m), respectively. The most common adverse events were neutropenia, sensory neuropathy, and nausea/vomiting. Grade 3 and 4 neutropenia were 22.3% and 11.7%, grade 3 sensory neuropathy was 5%. The patients with grade 3 and 4 neutropenia, and those with biochemical response (50% reduction of CA19-9) achieved better ORR (75% and 76.7%, respectively). Of 52 patients with elevated CA19-9 at baseline, 32 patients (61.5%) had biochemical response showed a better median OS than those without the biochemical response (15.9 m versus 5.7 m, P=0.029). Conclusions: Nab-paclitaxel plus S-1 showed encouraging ORR and being tolerated. Future phase III randomized clinical trial in advanced PAC is warranted. Clinical trial information: NCT02124317. [Table: see text]
Real world treatment utilization and outcomes of patients with metastatic bladder cancer by cisplatin eligibility in U.S. community oncology practice.
Authors: Flannery Kyle , Black-Shinn Jenny , Boyd Marley , Kamat Ashish M. 
Published: September 2018

e16016 Background: Cisplatin(cis)-based therapy is standard first-line (1L) treatment for patients (pts) with metastatic bladder cancer (mBC). Many pts are cis-ineligible mostly due to reduced renal function (creatinine clearance (CrCl) < 60) or ECOG PS of 2 or greater (ECOG2+). Methods: We retrospectively identified mBC pts treated from Jan 2010 – June 2014 fromelectronic health records of McKesson Specialty Health/US Oncology, with follow-up through July 2016. Cis-ineligibility was identified using a consensus-based algorithm (pts with CrCl < 60 and/or ECOG2+ classified cis-ineligible). Results: 1155 pts received 1L treatment; median age 72 yrs (range 26-90+). The most common 1L regimens were cis/gemcitabine (gem) (26.8%), carboplatin (carbo)/gem (26.5%), carbo/paclitaxel (8.9%), and gem alone (8.3%). Among all pts, 55.2% were cis-ineligible. Cis-ineligible pts were older (mean 74.4 yrs vs 66.5 yrs; p < 0.0001). 48.7% of eligible pts did not receive cis, and 25.4% of cis-ineligible pts received cis-based therapy. Interestingly, among 1L cis/gem pts, 34.5 % had CrCl < 60 and 11.5% had ECOG2+. Median (95% CI) overall survival (OS) was affected by cis-eligibility and by 1L cis receipt as follows: eligible/received cis, 17.6 mos (15.1-23.6); eligible/no cis, 14.6 mos (11.5-16.7); ineligible/received cis, 13.4 mos (10.6-16.8); ineligible/no cis, 9.5 mos (8.2-11.4); (p < 0.0001). Conclusions: To date, this is the largest reported cohort of real-world mBC pts. Both cis-eligibility classification and 1L cis receipt were associated with longer OS, and both were approximately equivalent and additive in their magnitude of effect. Most pts were cis-ineligible; nonetheless, cis was used in one fourth of all cis-ineligible pts despite their classification. Cis-ineligible pts have high unmet medical need given their inferior survival.