bluuebunny/crossref_metadata_2025_split huggingface dataset:
Randomized phase III study of gemcitabine plus S-1 combination therapy versus gemcitabine plus cisplatin combination therapy in advanced biliary tract cancer: A Japan Clinical Oncology Group study (JCOG1113, FUGA-BT).
Authors: Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Katayama Hiroshi , Ueno Makoto , Ikeda Masafumi , Ozaka Masato , Sugimori Kazuya , Fukutomi Akira , Hara Hiroki , Mizuno Nobumasa , Yanagimoto Hiroaki , Sano Keiji , Tobimatsu Kazutoshi , Yane Kei , Nakamori Shoji , Sata Naohiro , Yukisawa Seigo , Ishii Hiroshi , Furuse Junji ,   Japan Clinical Oncology Group (JCOG)
Published: January 2019

205 Background: Gemcitabine (GEM) plus cisplatin (GC) is the standard of care for advanced biliary tract cancer (BTC). However, GC is considered to be toxic because of nausea, vomiting, and appetite loss, and inconvenient due to requiring hydration before and after administration. GEM plus S-1 (GS) was reported to be promising with preferable efficacy and acceptable toxicity profile (UMIN000001685). This phase III study aimed to confirm the non-inferiority of GS to GC in terms of overall survival (OS). Methods: Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable biliary tract adenocarcinoma (gallbladder, intrahepatic biliary tract, extrahepatic biliary tract, or ampulla of Vater), an ECOG-PS of 0–1, and adequate organ function. In the GC arm, 1 g/m2 of GEM and 25 mg/m2 of cisplatin was infused on days 1 and 8 of a 21-day cycle. In the GS arm, 1 g/m2 of GEM was infused on days 1 and 8, and S-1 60, 80, or 100 mg/day according to body-surface area was administered from days 1 to 14 of a 21-day cycle. The primary endpoint was OS and the secondary endpoints included progression-free survival (PFS), response rate (RR), adverse events (AEs), clinically relevant AEs defined as any of grade 2 or more fatigue, appetite loss, nausea, vomiting, oral mucositis, and diarrhea. The sample size was calculated to be 350 with a one-sided alpha of 5%, a power of 80%, non-inferiority margin of 1.155 in terms of hazard ratio (HR). Results: From May 2013 to March 2016, 354 patients were enrolled. The non-inferiority of GS to GC was demonstrated (median OS: 13.4 months (m) in GC and 15.1 m in GS, HR 0.95; 90% confidence interval (CI), 0.78 to 1.15; P = 0.046 for non-inferiority). Median PFS was 5.8 m in GC and 6.8 m in GS (HR 0.86, 95% CI, 0.70-1.07). RR was 32.4% in GC and 29.8% in GS. Preliminary AEs data demonstrated that both treatments were generally well tolerated, although clinically relevant AEs were observed 34.7% in GC and 31.2 % in GS. Conclusions: GS demonstrated non-inferiority to GC in OS with good tolerability and was considered as new convenient option of standard of care without hydration for advanced BTC. Clinical trial information: UMIN000010667.
Genomics-driven precision medicine for advanced pancreatic ductal carcinoma (PDAC): Early results from the COMPASS trial (NCT02750657).
Authors: Aung Kyaw Lwin , Fischer Sandra , Denroche Rob , Jang Gun Ho , Dodd Anna , Creighton Sean , O'Kane Grainne M. , Albaba Hamzeh , Moura Shari , Holter Spring , Moffitt Richard , Yeh Jen Jen , Krzyzanowski Paul , Dhani Neesha C. , Hedley David W. , Notta Faiyaz , Wilson Julie , Moore Malcolm J. , Gallinger Steven , Knox Jennifer J. 
Published: January 2019

211 Background: COMPASS is a prospective study with the primary aim to identify predictive mutational and transcriptional features in advanced PDAC for improved patient stratification and treatment selection. Methods: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy for whole genome sequencing (WGS) and RNA sequencing (RNASeq). Fresh tumor tissue was acquired by image guided percutaneous core needle biopsy of locally advanced primary or metastatic tumors. Laser capture microdissection was performed for all cases to ensure high-resolution genomic analyses. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Results: Of 63 patients who underwent a tumor biopsy between December 2015 and June 2017, WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Three patients with an ‘unstable’ genomic subtype, including two with a novel ‘duplicator’ phenotype, responded well to m-FOLFIRINOX. Of two cases with the same germline BRCA2 mutation, only the chemotherapy responder had loss of heterozygosity and genomic hallmarks of double stranded break repair deficiency. Approximately 25% of tumors displayed the basal-like RNA expression signature and these were chemotherapy resistant, with tumor shrinkage mainly observed in those with the classical RNA subtype (P = 0.003). Thirty percent of patients had potentially actionable genetic alterations. Conclusions: Prospective comprehensive genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes providing the impetus for further studies. Clinical trial information: NCT02750657.
A randomized phase 2 study of durvalumab monotherapy and in combination with tremelimumab in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC): ALPS study.
Authors: O'Reilly Eileen Mary , Oh Do-Youn , Dhani Neesha , Renouf Daniel John , Lee Myung Ah , Sun Weijing , Fisher George A. , Hezel Aram F. , Chang Shao-Chun , Vlahovic Gordana , Takahashi Osamu , Yang Yin , Philip Philip Agop 
Published: January 2019

217 Background: Durvalumab (D) and tremelimumab (T), monoclonal antibodies against PD-L1 and CTLA-4 immune checkpoints, have shown efficacy as monotherapy/combination therapy in multiple cancer types. Herein, we report a randomized phase 2 study to evaluate efficacy and safety of D monotherapy with or without T (D+T) in previously treated mPDAC. Methods: Part A was a lead-in safety and signal-seeking study with plans to expand to Part B as a nonrandomized or randomized controlled study pending efficacy signal. Eligible pts had progressive disease (PD) following front-line 5-FU- or gemcitabine-based therapy. In Part A, pts were randomized to D (1.5 g IV Q4W) or D+T (D 1.5 g IV + T 75 mg IV Q4W × 4 doses → D 1.5 g IV Q4W) for up to 12 months (mo) or until confirmed PD or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate per RECIST 1.1. Results: In Part A, 65 pts were randomized to D (n = 33) or D+T (n = 32). Due to a pretreatment death, 64 pts received therapy. Eleven pts (34.4%) in D+T and 10 (31.3%) in D had treatment-related adverse events (trAEs); 7 (22%) in D+T and 2 (6%) in D had grade ≥3 trAEs. Common trAEs: fatigue (12.5%), diarrhea (12.5%), and hypothyroidism (9.4%) in D+T; fatigue (9.4%), diarrhea (6.3%), and pruritus (6.3%) in D. Grade ≥3 trAEs were diarrhea (9.4%), fatigue (6.3%) in D+T and ascites (3.1%), hepatitis (3.1%), and increased lipase (3.1%) in D. In D+T, 3 (9.4%) pts and 1 (3.1%) in D discontinued therapy due to trAEs. No trAEs resulted in death. In D+T, 1 (3.1%) pt had a durable confirmed partial response (PR) > 12 mo and disease control rate (DCR) was 9.4%. In D, 2 (6.1%) pts had unconfirmed PRs, and the DCR was 6.1%. Median PFS in both arms was 1.5 mo, and median OS was 3.1 mo in D+T and 3.6 mo in D. Biomarker analyses (tumor mutation burden, PD-L1 and microsatellite status) are currently being evaluated. Conclusions: Typical safety profiles were observed for D or D+T in mPDAC. Part B was not enrolled as the threshold for efficacy was not met in Part A. D and D+T had modest activity in second-line non-selected mPDAC, underpinning the need for multimodal immune-based combinations to overcome intrinsic resistance in this disease. Clinical trial information: NCT02558894.
High neutrophil-to-lymphocyte ratio as an independent adverse prognostic factor in racial minorities with hepatocellular carcinoma.
Authors: Thibaud Santiago , Aparo Santiago , Chuy Jennifer W. , Kaubisch Andreas 
Published: January 2019

218 Background: An elevated neutrophil-to-lymphocyte ratio (NLR) has been shown to portend poor prognosis in various types of cancer, including hepatocellular carcinoma (HCC). However, studies that evaluated the prognostic significance of NLR did not include large numbers of Blacks and Hispanics. This single-center, retrospective study conducted on a large, racially diverse cohort explores the utility of NLR in predicting outcomes in minority populations. Methods: We identified patients (pts) diagnosed with HCC at our institution between the years 2000 and 2016. We calculated NLR at the time of diagnosis and divided pts into two groups: high NLR (NLR > 3) and low NLR (NLR ≤3). Demographics, clinical characteristics, MELD/MELD-Na scores, ALBI scores and AFP levels were collected. Survival analysis was conducted using the Kaplan-Meier method. Cox proportional-hazards model was used for multivariate analysis. Results: 751 pts with HCC were included in this study. 542 (72%) were male. Median age was 61 years. 43% were Hispanic, 33% Black, 22% White and 2% Other. NLR was high in 246 pts (32.7%, mean 6.0 ± 3.8) and low in 505 pts (67.2%, mean 1.69 ± 0.7). Overall survival (OS) was significantly lower in the high NLR group (median survival 25.4 vs 49.6 months, HR 1.75, 95% CI 1.41-2.17, P < 0.01). Subgroup analysis showed differences remained significant in the Hispanic group (n = 259, HR 1.93, 95% CI 1.30-2.86, P < 0.01) and the Black group (n = 194, HR 1.99, 95% CI 1.28-3.09, P < 0.01). The high NLR group had significantly higher MELD scores (mean 12.1 ± 5.0 vs 10.1 ± 3.8, P < 0.01), MELD-Na scores (13.9 ± 5.6 vs 11.3 ± 4.4, P < 0.01), ALBI scores (-2.05 ± 0.7 vs -2.28 ± 0.6, P < 0.01) and AFP levels (median 28.9 vs 46.9, P = 0.02). An NLR > 3 on multivariate analysis remained significantly associated with worse OS (HR 1.31; 95% CI 1.03-1.68; P = 0.02) after adjusting for age, gender, AFP and MELD-Na. Conclusions: NLR > 3 at the time of diagnosis had a strong correlation with poor OS in a large, racially diverse cohort of pts with HCC. This correlation held true for both Hispanic and Black patients, who have been previously underrepresented in similar studies. Our findings support the utility of NLR as a prognostic tool in HCC.
SMAD4 mutation acquisition in the metastatic transformation of pancreatic cancer.
Authors: Grewal Amardeep , Ben-Josef Edgar 
Published: January 2019

227 Background: SMAD4 mutations have been associated with worse prognosis and metastatic disease in patients with pancreatic cancer. It is unknown whether pancreatic cancers that metastasize acquire this mutation at disease onset or closer to the time of metastatic progression. Methods: Biopsies from 26 patients with known resectable and unresectable pancreatic cancer were analyzed via next generation DNA sequencing for 153 mutations associated with solid tumors, including SMAD4. Imaging and clinical data regarding extent of disease were reviewed at the time of each specimen collection. Results: 46% of patients had metastatic disease at the time of initial biopsy, and of these patients 83% had detectable SMAD4 mutations. Amongst patients with no evidence of metastatic disease, 11 of 14 had intact SMAD4. SMAD4 mutations were associated with metastatic spread of disease, Χ2= 7.46, p = .006. Eight patients with localized, SMAD4 intact pancreatic cancer had repeat biopsies at the time of metastatic progression that showed SMAD4 mutations not previously identified at the time of diagnosis. 2 of 3 patients with SMAD4 mutations and localized disease at diagnosis, developed metastatic disease within 7 months of biopsy. Mean time to metastatic disease development in localized disease patients with mutated and intact SMAD4 were 3.15 and 17 months, respectively, p = .01. Mean CA 19-9 levels in patients with mutated and intact SMAD4 were 10172 and 4117 U/mL, respectively, p = .04. Non-metastatic patients with SMAD4 mutations who developed metastatic disease shortly after initial biopsy only developed rising CA 19-9 levels once radiographic metastases were visible. Conclusions: SMAD4 mutations were ultimately acquired by each patient who presented with localized disease and then developed metastases, and are likely involved in the transformation from localized to metastatic disease. SMAD4 mutations are statistically associated with an earlier time to metastatic disease development in patients with localized disease at diagnosis. SMAD4 mutations precede CA 19-9 elevations in patients that develop metastatic disease and may represent a more sensitive biomarker to identify patients at greater risk for developing metastatic disease.
Discovery and validation of a quantitative, stromal-associated imaging biomarker of pancreatic ductal adenocarcinoma (PDAC).
Authors: Zaid Mohamed , Chaudhury Baishali , Varadhachary Gauri R. , Katz Matthew H. G. , Herman Joseph M. , Tamm Eric P. , Koay Eugene Jon 
Published: January 2019

228 Background: As pancreatic ductal adenocarcinoma (PDAC) remains highly lethal, biomarkers are needed to identify patients who may benefit from specific therapeutic strategies. We previously described a qualitative computed tomography (CT) based biomarker - delta classification, whereby high delta tumors showed lower stromal content, more aggressive biology and poorer outcomes, than their counterparts. Here, we describe a quantitative method to differentiate these patients and predict outcomes. Methods: We retrospectively identified 101 treatment naïve patients who underwent pancreatectomy as a discovery cohort and 90 patients who underwent preoperative gemcitabine-based chemoradiation for validation. All patients underwent a pre-therapy pancreatic protocol CT and were classified as high or low delta, as described before. We semi-automatically segmented the tumors, chose normal pancreatic (NP) tissue and abdominal fat as references, then measured relative enhancement values using Philips IntelliSpace8 multimodality tumor tracking. We then analyzed the arterial and portal-venous phases separately using ROC and cox proportional hazards. Results: Delta class significantly associated with normalized enhancement values (NEV) in the arterial phase referenced to NP (P<0.0001, AUC =90%). A cutoff of 0.72 was identified that also distinguished high and low delta groups in the validation cohort (P<0.0001). As a continuous variable, the NEV was associated with distant metastasis free survival (DMFS) and overall survival (OS) on uni and multivariate analyses, accounting for traditional survival covariates. Using cutoff of 0.72, patients with high NEV had longer median OS (39 and 35.9 months) compared to those with low NEV (17.5 and 17.6 months, P=<0.0001) in discovery and validation cohorts, respectively. Similarly, patients with high NEV had longer median DMFS (46.6 and 62.2 months) compared to those with low NEV (15.6 and 13.1 months, P=0.005) in discovery and validation cohorts, respectively. Conclusions: The NEV measurement on baseline CT scans may serve as a quantitative imaging biomarker that can objectively reflect tumor biology and provide prognostic insight.
Clinical prognostic impact of depth and pattern of CA19-9 response at 8 weeks of 1st line gemcitabine based chemotherapy in metastatic/unresectable pancreatic adenocarcinoma.
Authors: Kim In-Ho , Jeong Eun-gyo , Jeong Jae kyun , Lee Myung Ah 
Published: January 2019

230 Background: To evaluate the prognostic impact of depth and pattern of carbohydrate antigen (CA19-9) response at 8 weeks of first-line gemcitabine based chemotherapy in metastatic/unresectable pancreatic adenocarcinoma. Methods: We retrospectively analysed 183 patients who received first-line palliative gemcitabine based chemotherapy. The patients were stratified into 4 groups according to CA19-9 response: group A was defined as above 50% decrease, group B was below 50% decrease, group C was below<50% increase, and group D was above 50% increase in CA19-9 levels. Overall survival (OS) and progression-free survival (PFS) were compared according to CA19-9 response. Results: The CA19-9 response at 8 weeks after gemcitabine based chemotherapy was significantly associated with OS and PFS (median OS and PFS: 13.2 and 6.7[group A], 10.2 and 5.4[B], 6.5 and 3.8[C], and 3.5 and 1.8[D] months, respectively; all P<0.001). For responding group (A&B), group A showed better OS and PFS than group B (all P<0.001). For non-responding group (C&D), group D showed poorer OS and PFS than group C (all P<0.001). In radiologic responding group, complete and partial response by RECIST, group A&B showed better OS and PFS than group C&D (OS,P=0.001; PFS,P=0.003). Moreover, group A had better survival outcome than group B (OS, 14.5[A] vs 11.6[B] months,P=0.011; PFS, 8.6[A] vs 5.6[B] months,P=0.025). In stable or progressive disease by RECIST, OS was significantly prolonged in group A&B than group C&D (OS, 6.5 vs 3.7 months,P=0.038). Group D showed poorer OS than group C (OS, 4.2 vs 2.3 months,P=0.027). The CA19-9 response was a powerful prognostic factor for all patients in responding and non-responding by RECIST. Conclusions: The depth of CA19-9 response at 8 weeks of 1st line gemcitabine based chemotherapy can be a powerful prognostic factor in pancreatic cancer. It also can be a prognostic factor in patients with same response on imaging study by RECIST.
Prospective evaluation of slow-pull with fanning technique in EUS-guided fine needle aspiration on pancreatic masses.
Authors: Lee Jae Min , Lee Hong Sik , Choi Seong ji , Min Geeho , Kim Woojung , Lee Jung Min , Kim Seung Han , Choi Hyuk Soon , Kim Eun Sun , Keum Bora , Jeen Yoon Tae , Chun Hoon Jai , Kim Chang Duck 
Published: January 2019

232 Background: Endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) is useful in obtaining pancreatic mass samples. Combination of modified techniques (slow-pull technique and fanning technique) may improve the sample quality obtained by EUS-FNA. We investigated the effectiveness of a slow-pull with fanning technique in EUS-FNA for pancreatic mass. Methods: This prospective comparative study investigated EUS-FNA for pancreatic solid masses from August 2015-July 2016. The pairwise specimens were alternately obtained using two techniques: standard suction or slow-pull with fanning for target pancreatic lesions. We compared the specimen quality, blood contamination, and diagnostic yield of these techniques. Results: Forty-eight consecutive patients were enrolled (29 men; mean age, 68.1±11.9 years), and 96 pancreatic mass specimens were obtained. The slow-pull with fanning technique had significantly superior diagnostic accuracy than the suction technique (88% vs. 71%, p = 0.044). Further, blood contamination significantly reduced when the slow-pull with fanning technique was used (ratio of no or few contamination, 77% vs. 56%, p = 0.041). In the subgroup analysis, tumor size and sampling technique were related to EUS-FNA diagnostic accuracy. Conclusions: The slow-pull with needle fanning technique showed a good diagnostic yield for EUS-FNA for pancreatic mass. It can be useful in performing EUS-guided sampling for diagnosing pancreatic disease.
A sensitive biomarker panel to distinguish pancreaticobiliary malignancies from benign disease.
Authors: Burnett Atuhani S. , Ajibade Dare , Peters Stephen , Ahlawat Sushil , Mahmoud Omar , Chokshi Ravi 
Published: January 2019

238 Background: Biliary strictures present a diagnostic challenge to differentiate benign disease from hepatopancreaticobiliary (HPB) malignancies. Cytology from Endoscopic retrograde cholangiopancreatography (ERCP) or Endoscopic ultrasound with fine needle aspiration (EUS-FNA) have both been plagued by poor sensitivity and high false negative rates. In a review of over 80 adjunct molecular biology tests that have been attempted on ERCP and EUS-FNA samples, four immunohistochemistry biomarkers with sensitivities ranging 74-80% were identified; von Hippel Lindau loss of expression (VHL), over-expression of insulin-like growth factor 2 mRNA-binding Protein 3 (IMP3), and EF-hand Calcium 2+ binding S100 subfamily members A4 (S100A4) and P (S100P). We sought to determine if these results could be validated in a tumor explant model and furthermore if combining these tests into a biomarker panel could boost overall diagnostic sensitivity to 100%. Methods: Tumor tissue and normal surrounding pancreas from 27 pancreaticoduodenectomy specimens were selected by an experienced pathologist, subjected to immunohistochemistry staining with VHL, IMP3, S100A4, S100P, and the intensity and percent of cells staining was graded. Using ROC curve analysis, threshold criteria were chosen for each biomarker to differentiate between tumor and normal pancreas. Biomarkers were then evaluated as a panel for their ability to discriminate malignant from benign specimens. Results: Individual sensitivity of VHL, IMP3, S100A4, and S100P were found to be 75.0%, 79.2%, 45.8%, and 0%. When VHL, IMP3, and S100A4 were grouped into a panel, they were able to distinguish cancer from normal tissue with a sensitivity of 100% and a specificity of 96%. S100P was dispensable in our assay and only VHL, IMP3, and S100A4 staining were required to achieve 100% sensitivity. Conclusions: A panel of three biomarkers, VHL, IMP3, and S100A4, were able to distinguish pancreatic cancer from surrounding normal tissue with 100% sensitivity in our tumor explant model. Prospective studies on patient biopsy specimens are required to further validate the clinical use of this biomarker panel.