bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: Phase III KEYNOTE-181 study.
Authors: Kojima Takashi , Muro Kei , Francois Eric , Hsu Chih-Hung , Moriwaki Toshikazu , Kim Sung-Bae , Lee Se-Hoon , Bennouna Jaafar , Kato Ken , Lin Shen , Qin Shi-Qui , Ferreira Paula , Doi Toshihiko , Adenis Antoine , Enzinger Peter C. , Shah Manish A. , Wang Ruixue , Bhagia Pooja , Kang S. Peter , Metges Jean-Philippe 
Published: January 2019

2 Background: Patients with advanced esophageal cancer after first-line chemotherapy (chemo) have a poor prognosis and limited treatment options. We present results of the phase 3 KEYNOTE-181 study of pembrolizumab vs investigator’s choice chemo as second-line therapy for patients (pts) with advanced/metastatic squamous cell carcinoma (SCC) and adenocarcinoma of the esophagus or Siewert type I adenocarcinoma of the EGJ (NCT02564263). Methods: Eligible pts were randomized 1:1 to pembrolizumab 200 mg Q3W for up to 2 years or investigator’s choice chemo of paclitaxel, docetaxel, or irinotecan. Randomization was stratified by histology (SCC vs adenocarcinoma) and region (Asia vs rest of world). Primary end points were OS in the SCC, PD-L1 combined positive score (CPS) ≥10, and ITT populations. Results: 628 pts were randomized including 401 with SCC, and 222 with CPS ≥10. As of October 15, 2018, the median follow-up was 7.1 mo (pembrolizumab) vs 6.9 mo (chemo). Pembrolizumab was superior to chemo for OS in CPS ≥10 (N=222; median 9.3 vs 6.7 mo; HR 0.69; 95% CI 0.52-0.93; P=0.0074). The 12-mo OS rate in pts with CPS ≥10 was 43% vs 20%. There was clinically meaningful improvement in OS with pembrolizumab vs chemo in pts with SCC, but this was not statistically significant per prespecified boundaries (N=401; 8.2 mo vs 7.1 mo; HR 0.78; 95% CI 0.63-0.96; P=0.0095). In the ITT population, while directionally favorable, the difference in OS was not statistically significant (N=628; 7.1 mo vs 7.1 mo; HR 0.89; 95% CI 0.75-1.05; P=0.0560). Fewer pts had any-grade (64% vs 86%) or grade 3-5 (18% vs 41%) drug-related AEs with pembrolizumab vs chemo. Conclusion: Pembrolizumab significantly improved OS compared with chemo as second-line therapy for advanced esophageal cancer with PD-L1 CPS ≥10, with a more favorable safety profile. These data support pembrolizumab as a new second-line standard of care for esophageal cancer with PD-L1 CPS ≥10. The phase 3 KEYNOTE-590 study of pembrolizumab plus chemo as first-line therapy for advanced esophageal cancer is ongoing (NCT03189719). Clinical trial information: NCT02564263.
Phase II trial of SM-88 in patients with metastatic pancreatic cancer: Preliminary results of the first stage.
Authors: Noel Marcus Smith , Wang-Gillam Andrea , Ocean Allyson J. , Chawla Sant P. , Del Priore Giuseppe , Picozzi Vincent J. 
Published: January 2019

200 Background: SM-88 (tyrosine derivative [Td], mTOR inhibitor, CYP3a4 inducer and oxidative stress catalyst) is a relatively non-toxic, targeted therapy that utilizes the Warburg Effect in combination with oxidative stress to cause tumor cell death. It is well suited for pancreas cancer because of its ability to penetrate tumors and be tolerated by debilitated patients. Methods: Patients progressed on at least one line of chemotherapy are eligible for either low versus high dose single agent SM-88 in the dose selecting first stage of this trial. The primary endpoint of the study is response rate by BICR (NCT03512756). Results: As of Sept 23, 36 subjects with initial stage II 26%, III 33%, or IV 41%, were randomized between an active Td dose (430 mg/d) and 920 mg/d. Mean age was 64.9 (45.6 - 84.1); BMI 24.2 (16.8 - 36.7); female 45.5%, white 93.1%, black 4.5%; median of 3 prior lines (range 1 - 6); baseline median albumin, neutrophil lymphocyte ratio, alk phos and 19.9 were 3.8 g/dl (2.6 - 9.6), 4 (1 - 141), 179.5 (54 - 661) and 5089 (4 - 651, 696) respectively. The regimen was well tolerated with no treatment related grade 4 or 5 events; 55.6% of treated subjects (20/36) had 94 AEs, with 18.0% (17/94) being at least possibly treatment related, of which three were grade 3 (arthralgia, fatigue and asthenia). CTCs at baseline were detected in 97% (mean 93.1 cells/4 ml) and fell in 69% (11/16) evaluable subjects from 141.4 to a nadir of 30.7/4 ml (median reduction 77% [3% - 97%]). 22.2% (2/9) evaluable subjects showed CA19.9 declines, both of which also showed CTC declines. 83% of subjects have remained on treatment a median of 4.7 wks (1 - 18.7); 6 were eligible for the initial scheduled assessment at 2 months; 3 of 4 evaluable subjects (75%) had RECIST or PET SUV responses. Lesion SUVs decreased an average of 24.1% (8.3 - 35.7%). EORTC QLQ-C30, -PAN26 and correlative assays were obtained including IGF, leptin, genomics, NLR, and others. Conclusions: SM-88 has demonstrated unconfirmed monotherapy efficacy signals with no meaningful toxicity in a preliminary assessment of this ongoing trial. With additional follow up a dose will be selected for expansion Clinical trial information: NCT03512756.
Meta-analysis of OS for pancreatic cancer patients receiving 5FU and oxaliplatin-based therapy after failing first-line gemcitabine-containing therapy.
Authors: Wainberg Zev A. , Feeney Kynan , Lee Myung Ah , Muñoz Martín Andres J. , Cubillo Gracián Antonio , Lonardi Sara , Ryoo Baek-Yeol , Hung Annie , Lin Yong , Bendell Johanna C. , Hecht J. Randolph 
Published: January 2019

202 Background: Pancreatic cancer is the 3rd most common cause of cancer-related death in US. After progression on first-line gemcitabine-based therapy, guidelines suggest that 5FU with nanoliposomal irinotecan/irinotecan is the preferred regimen. Oxaliplatin (OXA) is not endorsed as prominently, as conflicting results have emerged on the efficacy of 5FU/OXA. This large variability in efficacy outcomes may be due to the heterogeneity of patient performance status (PS) or other confounding factors. We performed a meta analysis in an attempt to estimate the median (m) OS of patients receiving 5FU/OXA-containing regiments after failing first-line treatment with gemcitabine-containing therapy. Methods: A systematic review of literature and existing meta analyses for second-line treatment of pancreatic cancer was performed. Selection inclusion criteria included: prior gemcitabine treatment, second-line treatment of locally advanced or metastatic pancreatic cancer, 5FU and OXA; exclusion criteria included: oral 5FU (S1), irinotecan, capecitabine/cisplatin, no ECOG disclosure. A Bayesian fixed effect meta analysis was performed for the mOS with PS as predictor. A non-informative prior was used to establish the relationship between mOS and PS. The posterior median of OS and 95% predictive interval (PI) were summarized. Results: Eleven studies (454 patients) met the selection criteria for analysis. Median OS for patients receiving second-line 5FU and OXA-based therapy with ECOG PS 0-1 was 6.2 months (95% PI 5.4, 7.1). Restricting to FOLFOX (6 studies, 258 patients), mOS was 6.3 months (95% PI, 5.4, 7.4). Median OS were comparable to those observed with nanoliposomal irinotecan (NAPOLI-1) where 90% patients had ECOG 0-1. Some of the most frequent ( > 10%) grade 3-4 AEs for 5FU and OXA included neutropenia, thrombocytopenia, anemia, and fatigue, comparable to that reported with irinotecan-based therapy. Conclusions: This meta analysis suggests that after progression on a first-line gemcitabine containing regimen, 5FU and OXA-based therapy (eg. FOLFOX) may be a viable and acceptable treatment for patients with pancreatic cancer with good PS.
CA19-9 decrease and overall survival according to platelet level in patients with metastatic pancreatic cancer.
Authors: Chen Yang , Dai Guanghai 
Published: January 2019

203 Background: Several studies have linked a decrease of carbohydrate antigen (CA) 19-9 to lengthened survival in pancreatic cancer. Experimental evidence supported that CA19-9 may be involved in platelet/tumor cell interactions. The object of this study was to correlate a decline in CA19-9 with survival according to platelet level in metastatic pancreatic cancer. Methods: A retrospective analysis of patients with histologically diagnosed metastatic pancreatic cancer was performed. CA19-9 serum concentration and platelet level was measured at baseline and every 6 weeks. Results: Total 174 metastatic pancreatic cancer patients with baseline and week-6 CA19-9 measurements were analyzed. Median follow-up from initial chemotherapy was 29.2 months, and median survival from initial chemotherapy was 6.7 months. Multivariate analyses confirmed an early decrease in CA19-9 concentrations of 25% after two cycles of chemotherapy were associated with a favorable survival compared with patients who did not have a decrease of 25% (HR = 0.56 [95% CI: 0.40-0.78]). The association of CA19-9 decrease with overall survival differed by platelet level ( Pinteraction < 0.001). Multivariable adjusted hazard rations for decrease in CA19-9 of 25% were 0.30 (0.18-0.49) in patients with low platelet level (PLT < 190 × 109/L) and 0.85 (0.53-1.35) in patients with high platelet level (PLT ≥ 190×109/L). Conclusions: In patients with MPC, 25% decrease at week-6 could be an early marker for prognosis. The association of CA19-9 decrease with pancreatic cancer survival is stronger in patients with platelet low tumors than platelet high tumors. Our findings suggest a differential prognostic effect of CA19-9 according to platelet level.
Suggestion of new nomogram including inflammatory marker for predicting invasive carcinoma in intraductal papillary mucinous neoplasm of the pancreas.
Authors: Han In Woong 
Published: January 2019

204 Background: Previous studies have analyzed that inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and advanced lung cancer inflammation index (ALI), associated with the presence of invasive carcinoma in patients with intraductal papillary mucinous neoplasm (IPMN). This study aimed to evaluate the correlation between the inflammatory markers and the invasive carcinoma in IPMN and propose a nomogram including inflammatory markers for predicting invasive IPMN. Methods: From 1995 to 2016, total 468 patients who underwent surgical resection at four institutions for histologically confirmed IPMN and the data were reviewed retrospectively. The patients with history of pancreatitis, other malignancies and without CA19-9 data or lymphocyte counts were excluded, the study cohort consisted of 365 patients. Variables with P < 0.05 in risk factor analysis were included in the nomogram. Results: Of 365 patients, 98 (26.8%) patients had invasive IPMN. In univariate analysis, high body mass index (BMI) ( P = 0.037), pre-operative bilirubin level ( P = 0.001), CA19-9 ( P < 0.001), NLR ( P = 0.019), PLR ( P = 0.002), ALI ( P = 0.001), main duct type (P < 0.001), the presence of solid portion ( P < 0.001) and tumor size (P = 0.086) were identified as risk factors for invasive IPMN. In multivariate analysis, pre-operative bilirubin level (P = 0.003), CA19-9 (P = 0.002), main duct type (P = 0.034) and the presence of solid portion (P < 0.001) were independent predictive markers for invasive IPMN. The nomogram was developed including all factors of risk factor analysis. Conclusions: The inflammatory markers were the risk factors for the presence of IPMN-associated invasive carcinoma. This nomogram may be useful in identifying patients with IPMN at risk of malignancy and for selecting which patients should undergo surgery. Further validation studies are needed to assess the predictive ability of nomogram including inflammatory markers.
The evaluation of the eighth edition of the AJCC/UICC staging system for intrahepatic cholangiocarcinoma: A proposal of a modified new staging system.
Authors: Yamamoto Yusuke , Sugiura Teiichi , Okamura Yukiyasu , Ito Takaaki , Ashida Ryo , Ogi Katsuhisa , Uesaka Katsuhiko 
Published: January 2019

206 Background: The objective was to clarify the prognostic impact of the 8th edition of American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) of intrahepatic cholangiocarcinoma (ICC). Methods: ICC patients who underwent hepatectomy for ICC between 2002 and 2016 were enrolled. The survival impact of AJCC/UICC 8th edition was examined. Results: A total of 103 resected patients were enrolled. The 5-year disease-specific survival (DSS) rate was 75.9% in T1a (n = 23), 88.9% in T1b (n = 10), 14.9% in T2 (n = 24), 52.5% in T3 (n = 11), and 15.2% in T4 (n = 35). The DSS was comparable among T2, T3, and T4 (p = 0.345, 0.295). The 5-year DSS was 87.5% in stage IA, 88.9% in IB, 18.1% in II, 66.7% in IIIA, and 15.0% in IIIB. The DSS rates of stage II and stage IIIB were comparable, and the DSS rate of stage II was worse than that of stage IIIB. A multivariate analysis identified multiple tumors (hazard ratio [HR]: 2.821), periductal infiltrating (HR: 2.439), perforation of the visceral peritoneum (HR: 1.850), and vascular invasion (HR: 1.872) as independent prognostic factors that were associated with the DSS. Lymph node metastasis (HR: 1.715) was not an independent prognostic factor. The optimum tumor size with the greatest difference in the DSS was 2 cm (p = 0.014). The new T classification was developed as follows: T1, size ≤ 2 cm without other factors; T2, size > 2 cm without other factors; T3, vascular invasion or perforation of the visceral peritoneum; and T4, multiple tumors or periductal infiltrating. The HR of lymph node metastasis was similar to that of the low-HR factors, so lymph node metastasis was categorized as Stage IIIA. The 5-year DSS was 100% in T1 (n = 7), 76.6% in T2 (n = 28), 45.1% in T3 (n = 28), and 3.4% in T4 (n = 40). There were differences in the DSS between T2 and T3 (p = 0.035) and between T3 and T4 (p = 0.003). The 5-year DSS was 100% in stage I, 85.6% in II, 42.4% in IIIA, and 3.4% in IIIB (Fig. 2d). There were significant differences in the DSS between stage II and IIIA (p = 0.013) and between IIIA and IIIB (p = 0.026). Conclusions: T2, T3, and T4 of AJCC/UICC overlapped with regard to the DSS. The new staging can classify ICC patients with sufficient prognostic differences.
Multiplatform profiling of pancreatic neuroendocrine tumors (PanNETs) identifies novel co-occurring pathogenic alterations and associations with clinicopathologic factors.
Authors: Guan Michelle , Gong Jun , Hendifar Andrew Eugene , Tuli Richard , Placencio-Hickok Veronica , Bender Joseph , Blais Edik Matthew , Petricoin Emanuel 
Published: January 2019

211 Background: We correlated genomic, proteomic, and molecular pathway alterations with clinicopathologic factors and identified novel co-occurring pathogenic alterations of potential clinical relevance to PanNET management through multi-omic profiling. Methods: Perthera, Inc. deploys an IRB-approved registry that was utilized in partnership with PanCAN’s “Know Your Tumor” program. PanNETs having undergone molecular profiling for precision matched therapeutic purposes were screened. We performed correlative analyses by pairwise comparisons between pathogenic alterations or altered molecular pathways and clinicopathologic variables. Hierarchical clustering was used to visualize associations. The Kaplan-Meier method was used to estimate overall survival (OS) and survival differences across variables were analyzed by the log-rank test. Results: We included 33 patients with predominantly locally advanced and metastatic PanNETs from 12/2014-1/2018. Chromatin remodeling pathway and MEN1 alterations by next-generation sequencing (NGS) were less associated with having high-grade PanNETs, while MEN1 alterations were also less associated with metastatic disease at diagnosis (all Fisher’s exact two-tailed p ≤ 0.05). Several molecular pathway or pathogenic alterations correlated with worse OS: DNA repair pathway (log-rank p = 0.0022), RB1 alterations by NGS (p = 0.018), and TP53 alterations by NGS (p = 0.01). There were several significant co-occurring alterations (Fisher’s exact p ≤ 0.05): ERCC1 expression by immunohistochemistry (IHC) and DAXX (NGS), RB1 (NGS) and DNA repair pathway (NGS), and TS (IHC) and cyclin-dependent kinase pathway (NGS). Having an altered chromatin remodeling pathway was less associated with having an altered receptor tyrosine kinase (RTK) signaling pathway (Fisher’s exact p ≤ 0.05). Conclusions: We identified several molecular signatures of potential clinical significance for therapeutic targeting and prognostication in PanNETs warranting prospective validation. Our findings are hypothesis generating and can inform larger molecular profiling efforts in PanNETs.
Impact of the distance from the root of the splenic artery to the tumor in patents with the pancreatic body/tail cancer.
Authors: Minagawa Takuya , Okamura Yukiyasu , Sugiura Teiichi , Ito Takaaki , Yamamoto Yusuke , Ashida Ryo , Ogi Katsuhisa , Uesaka Katsuhiko 
Published: January 2019

221 Background: The impact of the distance from the root of the splenic artery to the tumor (DST) on prognosis and selection of operative procedures in patients with pancreatic body/tail cancer remains to be unclear. Methods: Between 2008 and 2018, 98 and 17 patients who underwent distal pancreatectomy (DP) and DP with celiac axis resection (DP-CAR) for conventional pancreatic ductal carcinoma were retrospectively analyzed. DST (mm) was measured by preoperative CT scan images. The indications for DP-CAR are the following: tumor involvement of the common hepatic artery and/or the celiac artery or difficulty in keeping surgical margin at the stump of the splenic artery. Results: Patients with DST = 0 had longer operation time ( p = 0.005), greater amount of blood loss ( p= 0.002), and higher morbidity rate ( p= 0.010) than those with DST > 0. The rate of introducing adjuvant chemotherapy in the DST = 0 group was significantly lower than that in the DST > 0 group (50% vs. 82%, p= 0.012). The median survival time (MST) of the DST = 0 group was significantly worse than that of the DST > 0 group (20 vs. 56 months, p< 0.001). In contrast, there was no significant difference of MST between the groups of 0 < DST≤10 and DST > 10 ( p= 0.499). Multivariate analyses revealed that DST = 0 (HR 4.51, p= 0.001), preoperative CA19-9 ≥40 U/mL (HR 2.91, p= 0.032) and preoperative neutrophil-to-lymphocyte ratio ≥2.3 (HR 2.49, p= 0.001) were independent prognostic factors. Regarding to the operative procedures, DP-CAR was performed 12 out of 14 patients with DST = 0, and 5 out of 16 patients with 0 < DST≤10. In the DST = 0 group, DP-CAR presented greater amount of dissected lymph nodes, higher rate of R0 resection, and lower rate of recurrence despite they were not identified statistically significant. In the 0 < DST≤10 group, DP-CAR tended to need longer operative time and higher rate of blood transfusion compared to DP, while there was no difference of prognosis. Conclusions: Multidisciplinary treatment including DP-CAR should be warranted for patients with DST = 0, which was a prognostic indicator. If surgical margin at the root of the splenic artery is secured in patients with DST > 0, DP should be an acceptable procedure.
Sensitivity and specificity of the NETest: A validation study.
Authors: Al-Toubah Taymeyah E. , Cives Mauro , Valone Tiffany , Blue Kirsten , Strosberg Jonathan R. 
Published: January 2019

222 Background: Secretory tumor markers traditionally measured in patients with NET, such as chromogranin A, are lacking in sensitivity and specificity, and consequently are of limited clinical utility. The NETest, a novel blood multigene RNA transcript assay, has been found to be highly sensitive and specific. We sought to validate the sensitivity of the NETest in a population consisting of metastatic well-differentiated NETs, and evaluate the specificity of the test in a mixed population of metastatic non-NET GI malignancies and healthy individuals. Methods: 100 individuals consented to be tested, comprising of 49 patients with metastatic well-differentiated NETs of gastroenteropancreatic and lung origin, 25 patients with other gastrointestinal cancers, and 26 healthy individuals. Samples were sent in a blinded fashion to a central laboratory (Wren Laboratories). A NETest value of 0-13% was considered within normal range. Results: Using the ULN of 13%, the sensitivity of the NETest was 98% (CI 89%-100%) with 48 true positive results and one false negative. The overall specificity (in a mixed population of healthy individuals and non-NET cancer patients) was 63% (CI 49%-75%), with 32 true negative and 19 false positive results. Among the 26 healthy individuals the specificity was 81% (CI 62%-92%); among patients with other GI cancers, specificity was 44% (CI 27%-63%). Using an alternate and updated normal range of 0-20%, sensitivity was unchanged (98%), but specificity improved to 100% among healthy patients, and 64% among patients with other cancers. Conclusions: The sensitivity of the NETest is exceptionally high in a population of metastatic well-differentiated NETs. Specificity within a healthy population of patients is exceptionally high when using a normal range of 0-20%, and moderately high when using a normal range of 0-13%. Specificity is lower when evaluating patients with other GI malignancies. Clinical trial information: NCT02948946.
A blood-based assay for diagnosis of early-stage pancreatic cancer.
Authors: Ettrich Thomas Jens , Berger Andreas Wolfgang , Schwerdel Daniel , Reinacher-Schick Anke C. , Uhl Waldemar , Alguel Hana , Friess Helmut , Koenig Alexander , Ghadimi Michael , Gallmeier Eike , Bartsch Detlef K. , Geissler Michael , Staib Ludger , Tannapfel Andrea , Kleger Alexander , Seufferlein Thomas 
Published: January 2019

234 Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. Biomarker are needed to facilitate early and preferably noninvasive detection of PDAC, which directly may influence patients’ prognosis. Here we aimed to test a new biomarker combination for early PDAC, consisting of thrombospondin-2 (THBS2), CA19-9 and circulating tumor DNA (ctDNA) analysis. Methods: Thirty-nine patients with histologically proven and clearly resectable PDAC (recruited from the NEONAX trial, NCT02047513) were enrolled. Fifteen patients with benign pancreatic disease (intraductal papillary-mucinous neoplasms, IPMN) served as controls. Blood samples were collected prior treatment. KRAS genotyping was performed after isolation of ctDNA from plasma (QIAamp MinElute ccfDNA Kit, Qiagen) by digital droplet PCR ( KRAS Screening Multiplex Kit; QX200 system, both: Bio-Rad). Clinical data and CA 19-9 levels were assessed by ELISA (Roche); THBS2 values were determined by Quantikine ELISA Human Thrombospondin-2 (R&D Systems). Statistical analyses were done by using GraphPad Prism Version 7.00, GraphPad Software, Inc. Results: THBS2 had a c-statistic of 0.73 for all PDAC stages which was comparable to that of CA 19-9 (0.78). The c-statistic was improved to 0.94 by combining CA 19-9, THBS2 and total cfDNA amount. This marker combination performed best for all stages. C-statistics of defined PDAC stages was 0.93, 1.00 and 0.92 for stage I, stage II and stage III, respectively. Of note, the biggest improvement in sensitivity and specificity was seen for stage I PDAC. Here, c-statistic improved from 0.69 or 0.85 for CA 19-9 alone or the combination of CA 19-9 and THBS2, respectively, to 0.93 for the three-marker combination. Conclusions: These data underscore that CA 19-9, THBS2 and cfDNA marker combination constitutes a composite liquid biomarker for non-invasive diagnosis of early-stage PDAC with a remarkable specificity. Larger studies are needed to examine the power of this approach.