bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical outcomes in patients undergoing multiple self-expandable metallic stent placement by stent in stent technique for malignant gastric outlet obstruction.
Authors: MO Jinwon , Kim Jie-Hyun , Shin Seung Yong , Jung Da Hyun , Park Jae Jun , Youn Young Hoon , Park Hyojin
Published: January 2019

88

Background: Self-expandable metallic stent (SEMS) placement is widely used for relieving the obstructive symptoms of malignant gastric outlet obstruction (MGOO). The aims were to evaluate the efficacy and safety of multiple gastroduodenal stent placement by stent in stent technique and identify predictive factors about stent patency. Methods: We retrospectively analyzed data from 170 patients with GOO receiving SEMS by stent in stent technique from July 2006 to July 2018. Among them, 90 patients had been treated with gastroduodenal SEMS placement for MGOO. Technical and clinical success rates were evaluated. And, clinical outcomes with predictors of stent patency were also analyzed. Results: Among the subjects, 34.4% were treated with secondary SEMS placement, and 9.7% were treated with third SEMS placement because of the previous stent dysfunction. The median stent patency time was 15.7 weeks (range 0-89) in the first SEMS, 10.4 weeks (range 0-44) in the second SEMS, and 11.3 weeks (range 1-29) in the third SEMS. The technical and clinical success rate were 100% and 97.8% in the first SEMS, 100% and 90.3% in the second SEMS, 100% and 100% in the third SEMS. In multivariable analysis, the first SEMS placement of covered type including Comvi stent was correlated with prolonged stent patency (OR 4.549, P = 0.001). And both chemotherapy after the first SEMS placement (OR 8.248, P = 0.006) and chemotherapy after the second SEMS placement (OR 7.467, P = 0.003) were correlated with prolonged stent patency. Serious complications such as gastrointestinal hemorrhage or perforation did not occur in any patient. Conclusions: Secondary and third gastroduodenal SEMS placement by stent in stent technique is a safe and effective treatment for the first stent dysfunction in MGOO. The stent placement of covered type and chemotherapy after stent placement is the predictor of stent patency. Keywords: Malignant gastric outlet obstruction, Self-expandable metallic stent, Stent in stent technique, Stent patency, Predictive factor
Phase I results from the phase 1/3 FIGHT study evaluating bemarituzumab and mFOLFOX6 in advanced gastric/GEJ cancer (GC).
Authors: Tejani Mohamedtaki Abdulaziz , Cheung Eric , Eisenberg Peter D. , Scott Aaron James , Tesfaye Anteneh A. , Dreiling Lyndah , Eng Clarence , Marina Neyssa , Mitra Siddhartha , Xiang Hong , Yan Xiaohong , Catenacci Daniel V.T.
Published: January 2019

91

Background: GC with FGFR2b overexpression or FGFR2 amplification is associated with a poor prognosis. Bemarituzumab (bema, FPA144) is a first-in-class humanized monoclonal IgG1 antibody that selectively blocks FGFR2b and triggers antibody-dependent cell-mediated cytotoxicity. With favorable safety and activity as a single agent in 2L+ patients with FGFR2b+ GC, the global, randomized, double-blind, placebo-controlled FIGHT study (NCT03343301) is evaluating the front-line combination of bema with mFOLFOX6. We report here the results from the phase I evaluation of the combination. Methods: Patients (pts) with unresectable, locally advanced or metastatic gastrointestinal malignancy (irrespective of FGFR2b status) for whom mFOLFOX6 would be appropriate were eligible for enrollment in the phase I. Her2+ disease or prior treatment with FGF-FGFR inhibitors was not allowed. All pts in the Phase 1 received mFOLFOX6 combined with bema in Q2W cycles. Cohort 1 (3+3) began with bema 6 mg/kg and cohort 2 (Rolling-6) bema 15 mg/kg with one dose of 7.5 mg/kg on C1D8. A dose-limiting toxicity (DLT) evaluation window of 28 days was used for both cohorts. Results: Cohorts 1 and 2 treated 3 pts and 9 pts respectively with a median of 4 and 2 prior lines of therapy. As of the iDMC data-cut on July 24, 2018, the median duration of treatment was 15 wks for cohort 1 and 4 wks for cohort 2; 6/9 pts in cohort 2 continue on treatment. No DLTs were identified. No adverse events (AEs) led to treatment discontinuation. There were no newly identified bema-related toxicities and the only ≥ Gr 2 AE attributable to bema in cohort 2 was fatigue (1 pt/Gr 2). The most common AEs overall were fatigue (6 pts/50%), nausea, vomiting and diarrhea (5 pts/42% each) and were generally attributed to FOLFOX or underlying disease. The ≥ Gr 3 AEs present in ≥ 1 pt were fatigue and neutropenia (2 pts/Gr 3 each). mFOLFOX6 did not affect bema exposure and all evaluable pts in cohort 2 achieved the target ≥ 60 µg/mL trough concentration by day 15. 2/7 pts at the data-cut had FGFR2b+ GC. Conclusions: Bema in combination with mFOLFOX6 has acceptable safety to proceed with the cohort 2 dose to the phase III portion of the FIGHT trial in previously untreated patients with FGFR2b+ GC. Clinical trial information: NCT03343301.
Primary results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) as neoadjuvant chemotherapy for locally advanced gastric cancer.
Authors: Yoshikawa Takaki , Sakamaki Kentaro , Nishikawa Kazuhiro , Fujitani Kazumasa , Tanabe Kazuaki , Ito Yuichi , Matsui Takanori , Miki Akira , Nemoto Hiroshi , Fukunaga Tetsu , Kimura Yutaka , Hirabayashi Naoki , Hayashi Tsutomu
Published: January 2019

93

Background: Neoadjuvant chemotherapy is promising to improve the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both active for metastatic gastric cancer. Methods: We conducted a randomized phase II trial to compare two and four courses of neoadjuvant S-1/cisplatin (SC) and docetaxel/cisplatin/S-1 (DCS) using a two-by-two factorial design for locally resectable advanced gastric cancer. Patients with M0 and either T4 or T3 in case of junctional cancer or schirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as neoadjuvant chemotherapy. Then, patients underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was 3-year overall survival. The planned sample size was 120 eligible patients in total so that the treatment group with the superior observed 3-year OS rate by more than 60% as compared with 50% of the control group was to be selected with a probability of 85% or higher. Results: Between October 2011 and September 2014, 132 patients were assigned to CS (n = 66; 33 in 2-courses and 33 in 4-courses) and DCS (n = 66; 33 in 2-courses and 33 in 4-courses). The 3-year OS was 58.1% (95% CI, 45.8-70.3%) in CS and 60.0% (95% CI, 48.0-71.9%) in DCS with hazard ratio of 0796 (95% CI, 0.475-1.335), while that was 53.1% (95% CI, 40.9-65.4%) in the two courses and 65.0% (95% CI, 53.2-76.8%) in the four courses with hazard ratio of 0.722 (95% CI, 0.429-1.216). In the survival analysis by duration in each regimen, the 3-year OS was 58.1% (95% CI, 45.8-70.3%) both for two and four courses in CS, while that was 48.5% (95% CI, 31.4-65.5%) for two courses of DCS and was 71.9% (95% CI, 56.3-87.5%) for four courses of DCS. Conclusions: Considering high 3-year OS, four courses DCS has a value to be tested in a future phase III study to confirm superiority of neoadjuvant chemotherapy for locally advanced gastric cancer. Clinical trial information: UMIN000006378.
A phase III, double-blind, randomized study of pamiparib versus placebo as maintenance therapy in patients with inoperable, locally advanced, or metastatic gastric cancer (GC) that responded to platinum-based first-line chemotherapy.
Authors: Ciardiello Fortunato , Bang Yung-Jue , Bendell Johanna C. , Cervantes Andres , Brachmann Rainer Karl , Zhang Yuting , Raponi Mitch , Farin Heinrich , Lin Shen
Published: January 2019

TPS173

Background: Gastric cancer is the fifth most common cancer, and is the third leading cause of cancer deaths worldwide. In patients with locally advanced or metastatic GC, fluoropyrimidine- and platinum-based combination chemotherapy is first-line standard of care. Despite refinement in chemotherapy regimens, outcomes are poor and survival after first-line treatment remains low. A subset of GCs exhibit platinum sensitivity and genomic instability that is characteristic of homologous recombination deficiency (HRD). Poly (ADP-ribose) polymerase proteins 1 and 2 (PARP1/2) are involved in DNA damage repair, and their inhibition is cytotoxic for cells with HRD. Pamiparib is a selective PARP1/2 inhibitor that crosses the blood-brain barrier, has shown potent DNA–PARP trapping, and has demonstrated antitumor activity in preclinical models. In early phase clinical studies (NCT02361723; NCT03333915), pamiparib was generally well tolerated and showed preliminary antitumor activity; 60 mg oral twice daily (BID) was established as the recommended dose. Methods: This ongoing, global, double-blind, placebo-controlled, randomized, multicenter phase III study (NCT03427814) is designed to compare the efficacy, safety, and tolerability of pamiparib vs placebo as maintenance therapy in ~540 patients with advanced GC who have responded to first-line, platinum-based chemotherapy. Patients who are ≤ 8 weeks after their last dose of first-line platinum based chemotherapy will be randomized 1:1 to receive either pamiparib 60 mg BID or placebo in 28-day cycles. Patient randomization will be stratified by genomic loss of heterozygosity status (ie, high vs low), region, and ECOG status. Radiologic assessments will be centrally evaluated per RECIST every 8 weeks after first dose. The primary endpoint is progression-free survival; key secondary endpoints include safety/tolerability, overall survival, objective response rates, time and duration of response, and time to second subsequent treatment. Correlative biomarker analyses in tumor tissues and blood will be performed. Clinical trial information: NCT03427814.
REVIVE study: Prospective observational study of efficacy and safety in chemotherapy (CTx) after progressive disease of nivolumab (NIV) therapy for metastatic gastric cancer (mGC).
Authors: Narita Yukiya , Shoji Hirokazu , Kawai Sadayuki , Mizukami Takuro , Nakamura Michio , Moriwaki Toshikazu , Yamanaka Takeharu , Sunakawa Yu , Kawakami Hisato , Nishina Tomohiro , Misumi Toshihiro , Yamashige Yu , Yamashige Akira , Muro Kei
Published: January 2019

TPS178

Background: Immune checkpoint inhibitors are drugs that block specific proteins produced by the immune system cells, such as T-cells; these proteins prevent T-cells from killing cancer cells. NIV is a standard care for pretreated mGC patients (pts), with increasing clinical use in Japan. Data from retrospective studies on various tumors have shown that after exposure to immune checkpoint inhibitors, the objective response rate to CTx potentially improves; however, enough data have not been accumulated. Although there are no recommended CTx regimen following NIV therapy, in a clinical setting, an irinotecan or oxaliplatin combination regimen (limited to cisplatin-refractory or cisplatin-intolerant pts) is frequently used as post-NIV CTx. This multicenter observational study aims to evaluate the efficacy and safety of CTx in NIV-refractory or NIV-intolerant mGC pts. Methods: We prospectively collect clinical and imaging data from NIV-pretreated mGC pts; these pts will be treated with cytotoxic agents. Pts who meet inclusion criteria A (histologically proven mGC pretreated with NIV, prior administration of a combination therapy of fluoropyrimidine plus platinum and taxanes, and written informed consent) at primary registration are registered. After primary registration, pts who meet inclusion criteria B [Eastern Cooperative Oncology Group Performance Status (ECOG PS 0-2), refractory or intolerant to NIV; prior administration of irinotecan monotherapy or oxaliplatin combination regimens and prior use of cisplatin; evaluable lesions according to RECIST ver. 1.1] at formal registration are registered. The primary endpoint is overall survival of NIV-pretreated mGC pts after CTx. For this study, we require 146 pts, with bilateral alpha = 0.05 and beta = 0.10, with a median threshold survival of 4.0 months and an expected median survival of 6.0 months. Therefore, we plan to enroll 200 pts, considering exclusions from the analysis; since May 2018, we have enrolled 27 pts. Clinical trial information: UMIN000032182.
A phase II, multicenter, open-label study of [fam-] trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing gastric cancer.
Authors: Shitara Kohei , Bang Yung-Jue , Chung Hyun Cheol , Yabusaki Hiroshi , Iwasa Satoru , Sakai Daisuke , Muro Kei , Sugimoto Naotoshi , Yasui Hisateru , Gamoh Makio , Murakawa Yasuko , Negoro Yuji , Nishina Tomohiro , Hosaka Hisashi , Omuro Yasushi , Kawaguchi Yoshinori , Sugihara Masahiro , Saito Kaku , Dalal Rita , Yamaguchi Kensei
Published: January 2019

TPS180

Background: There is no HER2-targeted therapy for patients with HER2-positive gastric cancer (GC) who progressed on trastuzumab-based therapy. [fam-] trastuzumab deruxtecan (DS-8201a) is a novel HER2-targeted antibody-drug conjugate with a humanized HER2 antibody, topoisomerase I inhibitor payload, cleavable peptide-based linker, and high drug-to-antibody ratio of approximately 8. In an ongoing phase I trial, [fam-] trastuzumab deruxtecan showed an acceptable safety profile and promising antitumor activity in salvage-line subjects with HER2+ GC who previously received trastuzumab (confirmed objective response rate [ORR] of 43.2% [19/44]; Iwata et al, ASCO 2018). Methods: The randomized, phase II, multicenter, open-label, DESTINY-Gastric01 study will assess the efficacy and safety of [fam-] trastuzumab deruxtecan in HER2-expressing GC. The primary cohort, HER2+ (IHC 3+ or IHC 2+/ISH+) GC subjects who progressed after ≥ 2 prior regimens and previously received trastuzumab, will be randomized (2:1) to [fam-] trastuzumab deruxtecan (6.4 mg/kg dose; once every 3 weeks) or physician’s choice (irinotecan or paclitaxel). Two nonrandomized exploratory cohorts will assess the efficacy and safety of [fam-] trastuzumab deruxtecan in subjects with HER2-low GC (IHC 2+/ISH- and IHC 1+, respectively) who are treatment-naïve to HER2-targeted therapies. The primary endpoint is ORR assessed by an independent central review; secondary endpoints include overall survival (OS), progression-free survival, duration of response, disease control rate, pharmacokinetics, and safety (as shown in ClinicalTrials.gov). The primary analysis for ORR and interim OS analysis will occur after all subjects complete tumor assessments on week 18 and when approximately 108 OS events are observed, whichever comes later. The primary cohort will enroll 180 subjects; providing 92.9% power to detect a difference between the ORR of 40% for [fam-] trastuzumab deruxtecan vs 15% for physician’s choice. Each exploratory cohort will enroll a maximum of 20 subjects. Enrollment began in October 2017. As of Feb 13, 2018, 12 of 180 subjects have been enrolled. Clinical trial information: NCT03329690.
NANT cancer vaccine an orchestration of immunogenic cell death by overcoming immune suppression and activating NK and T cell therapy in patients with third line or greater metastatic pancreatic cancer.
Authors: Seery Tara Elisabeth , Lee John H. , Sender Leonard S. , Jones Frank R. , Shinde Arvind Manohar , Annamalai Anand , Kistler Mira , Jafari Omid , Soon-Shiong Patrick
Published: January 2019

TPS463

Background: Pancreatic cancer has multiple mechanisms to prevent immune recognition that lead to the creation of an immune suppressive tumor microenvironment. We hypothesize that effective and sustained response against tumors requires a coordinated approach that: 1. reverses the immune-suppressive tumor microenvironment, 2. induces immunogenic tumor cell death and 3. reengages NK and T-cell tumor response against a 4. cascade of tumor antigens. To test this hypothesis, we developed the NANT Cancer Vaccine (NCV), which combines metronomic low-dose chemotherapy, radiotherapy and multifaceted immunotherapy. In proof-of-concept trials, the NCV was tested in 10 patients with 3rd-line or greater pancreatic cancer. These trials showed that the NCV could be safely administered in an outpatient setting, with AEs that were manageable by dose-reduction, and preliminary survival results that exceed the standard of care in this heavily-treated population. We believe these results warrant further research, and this abstract describes our newly-designed trial. Methods: A phase 1b, single-arm, open-label trial of the NANT Cancer Vaccine in patients with recurrent metastatic pancreatic cancer has been initiated. Treatment will occur in 3-week cycles of low-dose chemotherapy (aldoxorubicin, cyclophosphamide, oxaliplatin, nab-paclitaxel, 5-FU/L), antiangiogenic therapy (bevacizumab), SBRT, engineered allogeneic high affinity CD16 NK-92 cells (haNK), IL-15RαFc (N-803), adenoviral vector-based CEA vaccine (Ad-CEA), yeast vector-based RAS vaccine (Ye-RAS), and an IgG1 PD-L1 inhibitor, avelumab. The primary endpoint is incidence of treatment-related adverse events. Secondary endpoints include ORR, DCR, PFS, and OS. A maximum of 24 patients will be enrolled. Clinical trial information: NCT03586869.
Adjuvant chemotherapy of S-1 versus S-1 plus metformin for resected pancreatic cancer: A multicenter and randomized phase II trial.
Authors: Narita Masato , Furukawa Masayuki , Sakamoto Ichiro , Itoh Yutaka , Nakano Hiroshi , Naka Takuji , Sudo Takeshi , Yahara Noboru , Aoki Hideki , Oota Kouji , Matsumoto Toshifumi , Shimokawa Mototsugu , Hisano Terumasa
Published: January 2019

TPS474

Background: Adjuvant chemotherapy with S-1 in patients with resected pancreatic ductal adenocarcinoma (PDAC) improved the 5-year survival rate to 44.1% and therefore has been a standard of care in Japan. Recent epidemiologic data has revealed possibility of metformin (a drug for type II diabetes) improving the prognosis of PDAC. In this context, we compare the efficacy and safety of S-1 plus metformin with S-1 alone as adjuvant chemotherapy in patients with resected PDAC. Methods: This multicenter-randomized-phase II study is conducted at 29 institutions in Japan (Registry Number; UMIN000020681). Key eligibility criteria are age 20 years or more with good performance status; histologically proven PDAC of stage I-II without macroscopic residual tumor. Patients receiving preoperative treatment for PDAC and previously treated with DPP-4 inhibitor, GLP-1, and metformin are excluded. After giving written consent to the study, patients are randomly assigned either study group (S-1 plus metformin) or control group (S-1 alone), balancing residual tumor status, nodal status, and institutions. S-1 is given orally for 2 weeks in a 3-week cycle. Cycles are lasted for 6 months. In the study group, metformin is administrated together with S-1 for 2 years. The treatment would be discontinued when the patient has either recurrence or unacceptable toxicity. The primary endpoint is 2-year OS, and the secondary endpoints are relapse-free survival and incidence rate of adverse events. Sample size was calculated based on the data in previous trials, with an expected 2-year survival rate in the control group of 65%. An improvement in 2-year-survival rate from 65% in the control group to 78% in the study group, yielding a hazard ratio of 0.58, is considered clinically relevant in this population. A total of 73 events in each group were required for a power of 80% at a two-sided alpha 20% to detect a difference in OS using an unstratified log-rank test. A total of 160 patients (80 per group) were estimated to achieve the specified number of events in the scheduled follow-up. Duration of this study would be 5 years and it has been started from January 2018. Until September 2018, 17 patients have been enrolled. Clinical trial information: UMIN000020681.
Phase II randomized, double-blind, study of mFOLFIRINOX plus ramucirumab versus mFOLFIRINOX plus placebo in advanced pancreatic cancer patients hcrn GI14-198.
Authors: Shaib Walid Labib , O'Neil Bert , El-Rayes Bassel F. , Cohen Steven J. , Khair Tina Ashley , Robin Erwin L. , Huyck Timothy K. , Redman Rebecca A. , Sama Ashwin Reddy , Kassar Mohamad , Bekaii-Saab Tanios S.
Published: January 2019

TPS475

Background: The prognosis of pancreas adenocarcinoma (PCA) remains poor. A chemotherapy backbone is the current standard of care in PCA. The choice of a chemotherapeutic backbone may impact the efficacy of anti-angiogenic therapy in PCA. Ramucirumab has increased activity with fluoropyrimidines (5FU) because 5FU increases VEGF expression. Methods: This is a double-blind, placebo controlled Phase II study. Subjects will receive either Ramucirumab or a placebo followed by mFOLFIRINOX every two weeks of a 28 day cycle until progression or discontinuation for other reasons. The primary endpoint of this clinical trial is nine month PFS defined as the time from enrollment to the time of progression or death. Among the key inclusion criteria, subjects must have recurrent or metastatic pancreas adenocarcinoma (PCA) with no prior first-line systemic treatment, ECOG PS 0-1, adequate organ function, no DVT, PE or other thromboembolism within three months of randomization. Total number of patient enrolled as of September 19, 2018 is 48 of 85 at eight sites; 27 male (56%), 42 Caucasians (87.5%), three African American (6.2%), one Asian (2%). Median age is 63 (40 - 76). Majority of patients (41) had de novo metastatic disease and six with recurrent disease after surgery. Regimen has been tolerated well with no unanticipated events. Clinical trial information: NCT02581215.
A phase II study of ADI-PEG 20 and FOLFOX6 in patients (pts) with advanced hepatocellular carcinoma (HCC).
Authors: Harding James J. , Qin Shukui , Yang Tsai-Sheng , Yen Chia-Jui , Chao Yee , Wang Tsang-En , Do Richard K. G. , El Dika Imane H. , Uhlitskykh Khrystyna , Millang Brittanie M , Feng Xiaoxing , Swe Wint , Johnston Amanda , Bomalaski John S. , Li Chien-Feng , O'Reilly Eileen Mary , Ho Ching-Liang , Chen Yen-Yang , Abou-Alfa Ghassan K.
Published: January 2019

TPS477

Background: Arginine depletion interferes with pyrimidine metabolism as well as DNA damage repair pathways, and preclinical data indicate that pairing pegylated arginine deiminase (ADI-PEG 20) with fluoropyrimidines or platinum enhances cytotoxicity in vitro and in vivo in HCC models. A prior phase 1 study of FOLFOX6 and ADI-PEG 20 established the safety and recommended phase 2 dose of the combination in pts with advanced gastrointestinal tumors (Harding et al. CCP 2018). For 23 treatment-refractory HCC pts who were treated at the recommended phase 2 dose on an expansion cohort of the phase 1, the objective response rate (ORR) was 21% (95% CI 7.5-43.7) and median progression-free survival (PFS) was 7.3 months. These data were favorable when compared to historic data for FOLFOX alone where the ORR was ~8% and PFS was 2.93 months and suggest greater clinical activity of the combination (Qin et al. JCO 2013). Prospective confirmation of these results is required. Methods: This is an international, multicenter, single-arm, open-label phase 2 trial of ADI-PEG 20 and FOLFOX6 for advanced HCC pts with Child-Pugh A liver function who progressed on ≥ 2 prior lines of prior systemic therapy (NCT02102022). The primary objective is to define the ORR by RECIST 1.1 as assessed by blinded independent central review. Secondary objectives include determination of safety, disease control rate (DCR), duration of response (DOR), PFS, overall survival (OS), serum arginine, citrulline and anti-ADI-PEG 20 levels over 24 weeks, and alpha-fetoprotein response. Eligible pts receive intravenous FOLFOX6 biweekly at standard doses and ADI-PEG 20 intramuscularly weekly at 36 mg/m.2 Cross-sectional imaging will be completed every 8 weeks until progression of disease. Based on a two-sided exact test of a one-sample proportion with an alpha of 0.05, under a presumed ORR of 22%, there is 80% power to yield 95% confidence interval of 15-26%, which will require 46 objective responses in 225 subjects. Futility will be assessed three times during the study based on having ORR data available for 56, 110, and 166 patients. This Phase 2 will be stopped for futility if the conditional power drops below 20% at any of these time points. Clinical trial information: NCT02102022.
Avenger 500, a phase III open-label randomized trial of the combination of CPI-613 with modified FOLFIRINOX (mFFX) versus FOLFIRINOX (FFX) in patients with metastatic adenocarcinoma of the pancreas.
Authors: Philip Philip Agop , Buyse Marc E. , Alistar Angela Tatiana , Rocha Lima Caio Max Sao Pedro , Luther Sanjeev , Pardee Timothy S. , Van Cutsem Eric
Published: January 2019

TPS479

Background: Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Current treatments using FOLFIRINOX and gemcitabine plus nab-paclitaxel, provide median survivals of 11.1 and 8.5 months, respectively. PDAC cells have altered metabolism. CPI-613 is a novel TCA cycle inhibitor that targets cancer cells. In a phase I study mFFX plus CPI-613 resulted in a 61% objective response rate with 3 of 18 patients achieving a complete response. Methods: Avenger 500 (NCT03504423) is an open-label randomized trial of CPI-613 plus mFFX versus FFX in untreated patients with metastatic PDAC. 500 patients will be randomized 1:1 between arms. The experimental arm comprises CPI-613 500 mg/m2 on day 1 and 3 of a 14-day cycle. The mFFX regimen is the standard dose and schedule of 5-Fluorouracil but reduced doses of oxaliplatin (65 mg/m²) and irinotecan (140 mg/m²). The control arm is standard dose FFX. There are two co-primary endpoints: Overall Response Rate (ORR, Complete Response + Partial Response). Best response within the first 12 cycles will be used for this determination, to be confirmed by independent, blinded, central review. Progression-Free Survival (PFS), is the second co-primary endpoint. Secondary endpoints are overall survival, duration of response and safety. Patient reported outcomes will be compared using the NCCN-FACT FHSI-18. An interim analysis will be done after 167 patients are evaluable for response. The difference in ORR will be tested using a Lan-DeMets Pocock type boundary for futility and efficacy. Futility will be declared if the difference in ORR between the arms is smaller than 5%, while efficacy will be declared if it is larger than 20%. The PFS hazard ratio will be tested using a Lan-DeMets O’Brien-Fleming type boundary. Efficacy will be declared if the hazard ratio is less than 0.48. The final analysis will be done with 500 patients randomized, when ~375 PFS events are available. Significance will be reached if the PFS hazard ratio is less than 0.80, or the difference in ORR is at least 11%. If the trial reaches significance for either primary endpoint, overall survival will be tested. Clinical trial information: NCT03504423.
A phase II clinical trial platform for sensitization testing using total neoadjuvant therapy (TNT) in rectal cancer: Nrg-GI002.
Authors: George Thomas J. , Yothers Greg , Rahma Osama E. , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Lucas Peter C. , Gollub Marc Jeffrey , Hall William Adrian , Kachnic Lisa A. , Vijayvergia Namrata , Wolmark Norman
Published: January 2019

TPS721

Background: Locally advanced rectal cancer (LARC) improvements have plateaued due to an inability to consistently deliver adjuvant therapy and effective novel therapies. Systematic testing of new chemotherapy and radiation sensitizers is needed to advance treatment outcomes. This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel experimental arms (EA) in LARC. The EAs are not intended for direct comparison, but rather to test a variety of sensitizers or hypotheses in a consistent and homogenous high-risk patient (pt) population with correlative biomarkers. Success of any EA will be determined by achievement of pathologic endpoints compared to a control arm. Methods: The NRG-GI002 trial serves as a modular platform to assess novel sensitizers to neoadjuvant chemotherapy and/or chemoradiotherapy (chemoRT) in LARC. Eligibility includes LARC with any ONE of the following: distal location (cT3-4 ≤ 5 cm from anal verge, any N); bulky (any cT4 or tumor within 3 mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, pts receive neoadjuvant FOLFOX x 4 mo→chemoRT (capecitabine with 50.4 Gy)→surgical resection 8-12 wks later. The first EA will assess activity of veliparib with standard chemoRT. Enrollment to this EA is complete (results anticipated late 2019). The second EA, testing pembrolizumab concurrently with and following chemoRT, is currently active, with several other EAs in development. Primary endpoint is demonstrated improvement in Neoadjuvant Rectal Cancer score for the EA v control representing a 20% relative risk reduction in DFS HR and 3-4% absolute OS improvement. Secondary endpoints include comparisons of OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, sphincter function including QOL, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts/arm with additional EAs added through protocol amendments. NCT02921256. Support: U10CA180868, -180822, UG1-189867, U24-196067; AbbVie, Merck. Clinical trial information: NCT02921256.
JAK/STAT signaling in stem cells and regeneration: fromDrosophilato vertebrates
Authors: Herrera Salvador C. , Bach Erika A.
Published: January 2019

The JAK/STAT pathway is a conserved metazoan signaling system that transduces cues from extracellular cytokines into transcriptional changes in the nucleus. JAK/STAT signaling is best known for its roles in immunity. However, recent work has demonstrated that it also regulates critical homeostatic processes in germline and somatic stem cells, as well as regenerative processes in several tissues, including the gonad, intestine and appendages. Here, we provide an overview of JAK/STAT signaling in stem cells and regeneration, focusing on Drosophila and highlighting JAK/STAT pathway functions in proliferation, survival and cell competition that are conserved between Drosophila and vertebrates.
Au Supracrystal Growth Processes: Unexpected Morphologies
Authors: Pileni M P
Published: January 2019

In this account we describe the various morphologies of crystalline structures called supracrystals of 5 nm Au nanocrystals used as building blocks. The Au nanocrystals are coated with dodecanthiol, except when it is mentioned in the text. It is shown that traces of water molecules markedly change the average distance between nanocrystals. Similarly, the way to solvent evaporation, solvent vapor pressure and excess of coating agents induces a transition from films to shaped supracrystals. Furthermore, segregation between single domain and polycrystalline 5 nm Au nanocrystals takes place during the supracrystal formation. By mixing single domain Au and Co nanocrystals, vicinal surfaces are produced. A mechanism of such spontaneous formation of high index planes in Au single domain nanocrystal superlattices is proposed.
The Taxing Deed of Globalization
Authors: Egger Peter H. , Nigai Sergey , Strecker Nora M.
Published: January 2019

This paper examines the effects of globalization on the distribution of worker-specific labor taxes using a unique set of tax calculators. We find a differential effect of higher trade and factor mobility on relative tax burdens in 1980–1993 versus 1994–2007 in the OECD. Prior to 1994, greater openness meant that higher income earners were taxed progressively more. However, after 1994, we document a globalization-induced rise in the labor income tax burden of the middle class, while the top 1 percent of workers and employees faced a reduction in their tax burden of 0.59–1.45 percentage points. (JEL D31, F16, F61, H22, H24)
Optimal Trend Inflation
Authors: Adam Klaus , Weber Henning
Published: January 2019

Sticky price models featuring heterogeneous firms and systematic firm-level productivity trends deliver radically different predictions for the optimal inflation rate than their popular homogenous-firm counterparts: (i) the optimal steady-state inflation rate generically differs from zero and (ii) inflation optimally responds to productivity disturbances. We show this by aggregating a heterogeneous-firm model with sticky prices in closed form. Using firm-level data from the US Census Bureau, we estimate the historically optimal inflation path for the US economy: the optimal inflation rate ranges between 1 percent and 3 percent per year and displays a downward trend over the period 1977–2015. (JEL C51, D24, D25, E31, E52)
Demand and Supply of Infrequent Payments as a Commitment Device: Evidence from Kenya
Authors: Casaburi Lorenzo , Macchiavello Rocco
Published: January 2019

Despite extensive evidence that preferences are often time-inconsistent, there is only scarce evidence of willingness to pay for commitment. Infrequent payments for frequently provided goods and services are a common feature of many markets and they may naturally provide commitment to save for lumpy expenses. Multiple experiments in the Kenyan dairy sector show that: (i) farmers are willing to incur sizable costs to receive infrequent payments as a commitment device, (ii) poor contract enforcement, however, limits competition among buyers in the supply of infrequent payments. We then present a model of demand and supply of infrequent payments and test its additional predictions. (JEL K12, L66, O13, O17, Q12, Q13)
Evaluation of stray radiation to the operator for five hand-held dental X-ray devices
Authors: Smith Richard , Tremblay Richard , Wardlaw Graeme M
Published: January 2019

Objectives:

Evaluate stray radiation to the operator, as represented by a plane within the significant zone of occupancy (SZO), produced by five models of hand-held intraoral dental X-ray devices (HIDXDs).

Methods:

The stray radiation for five models of HIDXDs was measured, using an anthropomorphic tissue-equivalent head phantom as a scattering object. An ionization chamber was used to measure the air kerma (μGy) at 63 positions in a 160 cm high by 60 cm wide plane that was 10 cm behind the X-ray device, identified as being within the SZO.

Results:

Based on the measured air kerma from stray radiation of five different HIDXDs, the estimated annual air kerma at all measured spatial positions was calculated. When calculated using a median air kerma of 0.8 mGy at the distal end of the cone, as typically required for digital image receptors, 1 the ranges for estimated annual air kerma in the SZO across the devices were 0.14–0.77 mGy for the median, 0.41–1.01 mGy for the mean, and 1.32–2.55 mGy for the maximum. Similarly, when calculated using a median air kerma of 1.6 mGy as typically required for D-speed film, 2 the ranges for estimated annual air kerma across the devices were 0.28–1.54 mGy for the median, 0.83–2.03 mGy for the mean, and 2.64–5.10 mGy for the maximum.

Conclusions:

From measured air kerma values of stray radiation in the SZO, estimated annual exposures to the operator for HIDXDs are expected to be greater than from conventional wall-mounted or portable devices activated from a protected area (at a distance or behind shielding). HIDXDs should therefore only be used when patient accessibility makes their use necessary and the use of a portable device on a stand or a wall-mounted device is not reasonably feasible. This approach would keep occupational radiation exposures of dental workers as low as reasonably achievable.
First record of the isopod Idotea hectica (Pallas, 1772) (Idoteidae) and of the brachyuran crab Matuta victor (Fabricius, 1781) (Matutidae) in the Hellenic waters
Authors: KONDYLATOS GERASIMOS , CORSINI-FOKA MARIA , PERAKIS EMMANOUIL
Published: January 2019

The presence and the establishment of Idotea hectica is reported for the first time in the Hellenic seas on the basis of three adult specimens and a juvenile collected from Posidonia oceanica meadows close to the main town of Rhodes Island, Aegean Sea. Common and contrasting characters between this and other species of the genera Idotea and Pentidotea are briefly discussed. Furthermore, following a westward expansion along the eastern Mediterranean coasts, Matuta victor was discovered for the first time in Hellenic waters on the basis of a single specimen from the northeast of Rhodes Island.
DOLORisk: study protocol for a multi-centre observational study to understand the risk factors and determinants of neuropathic pain
Authors: Pascal Mathilde M.V. , Themistocleous Andreas C. , Baron Ralf , Binder Andreas , Bouhassira Didier , Crombez Geert , Finnerup Nanna B. , Gierthmühlen Janne , Granovsky Yelena , Groop Leif , Hebert Harry L. , Jensen Troels S. , Johnsen Kristinn , McCarthy Mark I. , Meng Weihua , Palmer Colin N.A. , Rice Andrew S.C. , Serra Jordi , Solà Romà , Yarnitsky David , Smith Blair H. , Attal Nadine , Bennett David L.H.
Published: February 2019

Background: Neuropathic pain is an increasingly prevalent condition and has a major impact on health and quality of life. However, the risk factors for the development and maintenance of neuropathic pain are poorly understood. Clinical, genetic and psychosocial factors all contribute to chronic pain, but their interactions have not been studied in large cohorts. The DOLORisk study aims to study these factors.

Protocol: Multicentre cross-sectional and longitudinal cohorts covering the main causes leading to neuropathic pain (e.g. diabetes, surgery, chemotherapy, traumatic injury), as well as rare conditions, follow a common protocol for phenotyping of the participants. This core protocol correlates answers given by the participants on a set of questionnaires with the results of their genetic analyses. A smaller number of participants undergo deeper phenotyping procedures, including neurological examination, nerve conduction studies, threshold tracking, quantitative sensory testing, conditioned pain modulation and electroencephalography.

Ethics and dissemination: All studies have been approved by their regional ethics committees as required by national law. Results are disseminated through the DOLORisk website, scientific meetings, open-access publications, and in partnership with patient organisations.

Strengths and limitations:

Large cohorts covering many possible triggers for neuropathic pain

Multi-disciplinary approach to study the interaction of clinical, psychosocial and genetic risk factors

High comparability of the data across centres thanks to harmonised protocols

One limitation is that the length of the questionnaires might reduce the response rate and quality of responses of participants
The Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX) Version 2.0: Modelling in vitro electrical stimulation of brain tissue
Authors: Thornton Christopher , Hutchings Frances , Kaiser Marcus
Published: February 2019

Neuronal circuits can be modelled in detail allowing us to predict the effects of stimulation on individual neurons. Electrical stimulation of neuronal circuits in vitro and in vivo excites a range of neurons within the tissue and measurements of neural activity, e.g the local field potential (LFP), are again an aggregate of a large pool of cells. The previous version of our Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX) allowed for the simulation of the LFP generated by a patch of brain tissue. Here, we extend VERTEX to simulate the effect of electrical stimulation through a focal electric field. We observe both direct changes in neural activity and changes in synaptic plasticity. Testing our software in a model of a rat neocortical slice, we determine the currents contributing to the LFP, the effects of paired pulse stimulation to induce short term plasticity (STP), and the effect of theta burst stimulation (TBS) to induce long term potentiation (LTP).
Four Questions on the Digital Economy
Authors: Свистунов Василий , Svistunov Vasiliy , Лобачев Виталий , Lobachyev Vitaliy
Published: January 2019

The article is devoted to the analysis of the main modern trends of digitalization of the economies of the leading world powers. Particular attention is paid to the state of Affairs with the practice of information and communication technologies in the Russian Federation. The analysis of trends in the participation of the digital economy in the formation of GDP of a number of countries, including Russia. The impact of digitalization processes on the current state and further development of various spheres of management is assessed. The practice of development of strategic programs for the development of national economies, which determine the targets for the development and implementation of modern information technologies in various industries and activities to improve the efficiency of national socio-economic systems. The author’s position in determining the main features of the current state of the digital economy of Russia is based on the generalization of the results of studies conducted by a number of international companies, and is of practical importance in the study of the problem of the ongoing transformation of social and labor relations in the context of digitalization.
Recommendations for the treatment of schizophrenia with negative symptoms. Standards of pharmacotherapy by the Polish Psychiatric Association (Polskie Towarzystwo Psychiatryczne), part 2
Authors: Szulc Agata , Dudek Dominika , Samochowiec Jerzy , Wojnar Marcin , Heitzman Janusz , Gałecki Piotr
Published: January 2019

Współczesne podejście do leczenia schizofrenii zakłada zastosowanie wielokierunkowej interwencji terapeutycznej koniecznej do uzyskania pełnej remisji objawów i powrotu chorego do pełnego funkcjonowania psychospołecznego. Odpowiednio dobrana i zastosowana farmakoterapia nadal pełni kluczową rolę w terapii chorych na schizofrenię. W poprzednich dekadach (od lat 50. XX wieku) stosowanie leków przeciwpsychotycznych miało na celu głównie opanowanie objawów pozytywnych (agresja, pobudzenie). Kolejne dziesięciolecia (od lat 80.) przyniosły możliwość zastosowania leków nowej generacji o mniejszych działaniach niepożądanych. Niektóre z tych leków okazały się również pomocne w łagodzeniu objawów negatywnych, co dawało niektórym chorym szansę powrotu do normalnego funkcjonowania. Nadal jednak uważa się, że pacjenci chorujący na schizofrenię z dominującymi lub przetrwałymi objawami negatywnymi stanowią największe wyzwanie terapeutyczne. Charakteryzują się gorszym przebiegiem, rokowaniem i odpowiedzią na leczenie. Ciągle potrzeba nowych, bardziej skutecznych, celowanych na te objawy interwencji terapeutycznych. Niniejsza praca przedstawia międzynarodowe standardy i rekomendacje Polskiego Towarzystwa Psychiatrycznego w podejściu do skutecznego leczenia objawów negatywnych w przebiegu schizofrenii.
Intercontinental Liner Shipping Service Design
Authors: Wang Yadong , Meng Qiang , Kuang Haibo
Published: January 2019

Intercontinental liner container shipping service connects trades between different continents in the global logistic system. This paper proposes a single intercontinental service design problem that aims to jointly determine the optimal serviced ports from a set of candidate ports, the port rotation, the ship sailing speed on each voyage between adjacent serviced ports and the number of containers transported for each type of shipping demand. A mixed integer linear programming model is formulated for the proposed problem based on mild assumptions to maximize the service profit, which is calculated as the freight revenue minus the total operating cost that includes port stay cost, container handling cost, bunker consumption cost, and other ship operating costs. The formulated model is also able to produce a service route with a more general topological structure than the simple cycle or butterfly cycle routes considered in most current studies. In view of the unique features of the model, a tailored and exact branch-and-cut algorithm is developed based on Benders decomposition to expedite the model solution. Numerical experiments demonstrate the efficiency of the developed branch-and-cut algorithm and show the applicability of the proposed model for designing the intercontinental liner shipping services.

The e-companion is available at https://doi.org/10.1287/trsc.2018.0831 .
Making sense
Authors: O'Connor Anne , Dickinson Kath
Published: January 2019

Sensory experiences are vital to healthy brain development, explain Anne O'Connor and Dr Kath Dickinson in part one of a new series
We've explored… the world
Authors: Rawstrone Annette
Published: January 2019

Julia Donaldson's What the Ladybird Heard inspired one setting to send children postcards from across the globe. By Annette Rawstrone
EYFS Training: part 1: Going back to basics
Authors: Goddard Charlotte
Published: January 2019

In a new series updating our popular EYFS Training series from 2010, Charlotte Goddard looks at the EYFS, its underpinning principles and changes ahead in 2019
Effects of mechanical forces on osteogenesis and osteoclastogenesis in human periodontal ligament fibroblasts
Authors: Li M. , Zhang C. , Yang Y.
Published: January 2019

Objectives

Many in vitro studies have investigated the mechanism by which mechanical signals are transduced into biological signals that regulate bone homeostasis via periodontal ligament fibroblasts during orthodontic treatment, but the results have not been systematically reviewed. This review aims to do this, considering the parameters of various in vitro mechanical loading approaches and their effects on osteogenic and osteoclastogenic properties of periodontal ligament fibroblasts.

Methods

Specific keywords were used to search electronic databases (EMBASE, PubMed, and Web of Science) for English-language literature published between 1995 and 2017.

Results

A total of 26 studies from the 555 articles obtained via the database search were ultimately included, and four main types of biomechanical approach were identified. Compressive force is characterized by static and continuous application, whereas tensile force is mainly cyclic. Only nine studies investigated the mechanisms by which periodontal ligament fibroblasts transduce mechanical stimulus. The studies provided evidence from in vitro mechanical loading regimens that periodontal ligament fibroblasts play a unique and dominant role in the regulation of bone remodelling during orthodontic tooth movement.

Conclusion

Evidence from the reviewed studies described the characteristics of periodontal ligament fibroblasts exposed to mechanical force. This is expected to benefit subsequent research into periodontal ligament fibroblasts and to provide indirectly evidence-based insights regarding orthodontic treatment. Further studies should be performed to explore the effects of static tension on cytomechanical properties, better techniques for static compressive force loading, and deeper analysis of underlying regulatory systems. Cite this article: M. Li, C. Zhang, Y. Yang. Effects of mechanical forces on osteogenesis and osteoclastogenesis in human periodontal ligament fibroblasts: A systematic review of in vitro studies. Bone Joint Res 2019;8:19–31. DOI: 10.1302/2046-3758.81.BJR-2018-0060.R1.