bluuebunny/crossref_metadata_2025_split huggingface dataset:
BACCI: A phase II randomized, double-blind, placebo-controlled study of capecitabine bevacizumab plus atezolizumab versus capecitabine bevacizumab plus placebo in patients with refractory metastatic colorectal cancer.
Authors: Mettu Niharika B. , Niedzwiecki Donna , Boland Patrick McKay , Fakih Marwan , Arrowood Christy , Bolch Emily , Hurwitz Herbert , Grothey Axel 
Published: January 2019

TPS873 Background: Initial treatment of metastatic colorectal cancer (mCRC) involves a 5-fluorouracil based chemotherapy regimen, often in combination with anti-VEGF therapy. Upon disease progression, multiple studies have suggested a benefit for continued anti-VEGF therapy. There is increasing evidence that VEGF plays a role in cancer immune evasion. Targeting of inflammatory and immune checkpoints are attractive approaches to enhance the benefits of anti-VEGF therapy. The safety and activity of the anti-PD-L1 antibody atezolizumab with bevacizumab and with 5-FU, oxaliplatin, and bevacizumab have been recently reported; the combinations were well-tolerated and suggested clinical activity. Therefore, bevacizumab may increase the immunogenicity of colorectal cancers, and the combination of atezolizumab plus bevacizumab may be associated with clinically meaningful response rates and disease control. Furthermore, there may be candidate biomarkers that may identify those patients most likely to benefit from this combination. Methods: In this randomized, double-blind, multicenter, placebo-controlled phase II study, 135 patients with mCRC will be randomized 2:1 to receive capecitabine/bevacizumab/atezolizumab or capecitabine/bevacizumab/placebo. Patients with prior PD-L1/PD-1 therapy are ineligible. Primary and secondary efficacy will be conducted using ITT analysis. Safety analyses will include all randomized patients who receive at least one dose of study treatment. The primary objective is PFS. The secondary objectives are ORR, OS, safety, and tolerability. The primary comparison will be superiority of the active treatment for the PFS endpoint, atezolizumab versus placebo testing at 1-sided α = 0.1 (log rank test). A PFS hazard ratio of 0.618 (active treatment versus placebo) is detectable with 86% power (1 sided α = 0.1). No interim analyses for futility or efficacy will be conducted. A subset analysis will be performed in the microsatellite-high patients looking at potential differences in PFS and OS. Trial is active and currently recruiting patients. Clinical trial information: NCT02873195.
NRG-GI002: A phase II clinical trial platform for sensitization testing using total neoadjuvant therapy (TNT) in rectal cancer.
Authors: George Thomas J. , Yothers Greg , Hong Theodore S. , Russell Marcia McGory , You Y. Nancy , Parker William , Jacobs Samuel A. , Pogue-Geile Katherine L. , Gollub Marc Jeffrey , Hall William Adrian , Rahma Osama E. , Kachnic Lisa A. , Vijayvergia Namrata , Wolmark Norman 
Published: January 2019

TPS876 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 are needed to advance treatment outcomes. This randomized phase II modular clinical trial platform utilizes Total Neoadjuvant Therapy (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: This NCTN multi-arm randomized phase II 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 criteria: distal location (cT3-4 ≤5cm from the anal verge, any N); bulky (any cT4 or tumor within 3mm of the mesorectal fascia); high risk for metastatic disease (cN2); or not a candidate for sphincter-sparing surgical resection. After randomization, all pts receive neoadjuvant FOLFOX x 4mo → chemoRT (capecitabine with 50.4Gy) → surgical resection 8-12 wks later. The first EA will assess the activity of veliparib with standard chemoRT. A second EA, testing pembrolizumab concurrently with and following chemoRT, is in development. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score for the EA vs 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 quality of life, and exploratory assessments of molecular and radiographic predictors of response and distant failure. Target accrual is 79 evaluable pts per arm with additional EAs added through protocol amendments. NCT02921256. Support: U10 CA-180868, -180822, UG-189867, U24CA196067; AbbVie Clinical trial information: NCT02921256..
KEYNOTE-177: Phase 3, open-label, randomized study of first-line pembrolizumab (Pembro) versus investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC).
Authors: Diaz Luis A. , Le Dung T. , Yoshino Takayuki , André Thierry , Bendell Johanna C. , Rosales Minori , Kang S. Peter , Lam Bao , Jäger Dirk 
Published: January 2019

TPS877 Background: Approximately 5% of mCRCs are dMMR, leading to high levels of MSI. CRCs with MSI-H have abundant lymphocyte infiltrates and strong expression of immune checkpoints. In the phase 2 KEYNOTE-016 study, the anti–programmed death 1 (PD-1) antibody pembro provided an ORR of 40% in patients (pts) with progressive dMMR mCRC vs 0% in pts with MMR-proficient mCRC. KEYNOTE-177 (ClinicalTrials.gov, NCT02563002) is an international, randomized, open-label, phase 3 study to evaluate the efficacy and safety of pembro vs standard-of-care (SOC) chemotherapy as first-line therapy for dMMR or MSI-H mCRC. Methods: Pts aged ≥18 years with locally confirmed dMMR or MSI-H stage IV CRC, measurable disease per RECIST v1.1 by local site assessment, ECOG performance status 0-1, adequate organ function, no active autoimmune disease or brain metastases, and no prior systemic therapy for mCRC are eligible. Pts will be randomized 1:1 to receive pembro 200 mg every 3 weeks (Q3W) or investigator’s choice of SOC chemotherapy (options include mFOLFOX6 or FOLFIRI alone or in combination with bevacizumab or cetuximab; must be chosen prior to randomization). Treatment will continue until disease progression, unacceptable toxicity, pt/investigator decision to withdrawal, or completion of 35 cycles (pembro only). Response will be evaluated Q9W per RECIST v1.1 by central imaging vendor review and per immune-related RECIST. Pts in the SOC arm who have disease progression and meet crossover criteria may be eligible to receive pembro for up to 17 treatment cycles. Eligible pts may continue pembro after initial RECIST-defined progression. AEs will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Pts are to be followed up for survival Q9W. Primary end point is PFS per RECIST v1.1 by central imaging vendor review. Secondary end points include ORR per RECIST v1.1 by central imaging vendor review, OS, and safety and tolerability. Other end points include DOR and HRQoL. Planned enrollment in KEYNOTE-177 is 270 pts across 23 countries. Clinical trial information: NCT02563002.
VOLTAGE: Multicenter phase 1b/II study of nivolumab monotherapy and subsequent radical surgery after preoperative chemoradiotherapy with capecitabine in patients with locally advanced rectal cancer.
Authors: Tsukada Yuichiro , Bando Hideaki , Inamori Koji , Fukuoka Shota , Sasaki Takeshi , Nishizawa Yuji , Kotani Daisuke , Kojima Motohiro , Togashi Yosuke , Nakamura Naoki , Akimoto Tetsuo , Komatsu Yoshito , Yuki Satoshi , Homma Shigenori , Hatanaka Yutaka , Matsuno Yoshihiro , Sato Akihiro , Nishikawa Hiroyoshi , Ito Masaaki , Yoshino Takayuki 
Published: January 2019

TPS878 Background: Fluoropyrimidine-based chemoradiotherapy (CRT) and subsequent radical surgery (SRS) are widely accepted as standard treatment for patients (pts) with locally advanced rectal cancer (LARC). Pathological complete remission (pCR) rates are associated with improved clinical outcomes. An important target, high-frequency microsatellite instability (MSI-H), was identified for which anti-PD-1 antibodies confirmed robust antitumor activity in metastatic colorectal cancer (mCRC). Recently, improved therapeutic effects by combining an immune checkpoint inhibitor with radiotherapy (RT) have been reported in pts with other cancer types. Furthermore, sequential use of an anti-PD-1 antibody after RT has demonstrated synergistic effects in in vivo models. The purpose of this study is to investigate safety, efficacy, and proof-of-concept (POC) of nivolumab (Nivo) monotherapy plus SRS after pre-CRT in non-MSI-H and MSI-H pts with LARC. Methods: The inclusion criteria are: LARC in the lower/middle rectum; clinical stage, T3–4 N-any M0; age ≥20 years; and 50.4 Gy of concurrent pre-CRT completed with daily 1,650 mg/m2 of capecitabine. Within 2 weeks after pre-CRT, 240 mg of Nivo is administered every 2 weeks 5 times before SRS, which is performed at least 2 weeks after Nivo treatment. The purpose of P1b is to evaluate dose-limiting toxicity and determine the recommended P2 dose (RP2D). In P2, the efficacy and safety of Nivo at RP2D are evaluated. The primary endpoint is the pCR rate by independent central assessment in pts with non-MSI-H LARC. Secondary endpoints include disease-free and overall survival and adverse events. Fifty pts including 40 non-MSI-H and 10 MSI-H pts will be enrolled. As an exploratory biomarker study, repeated biopsies from primary sites and blood collections will be performed 4 times during the treatment courses (before and after pre-CRT, during Nivo treatment, and at SRS), and phenotypes of immune-competent cells, neoantigens, T cell receptor repertoire, and enteric bacteria will be evaluated. As of September 2017, P1b has been completed and P2 is ongoing. Clinical trial information: NCT02948348.
TRUSTY: A randomized multicenter phase II/III study of trifluridine/tipiracil and bevacizumab versus irinotecan, fluoropyrimidine, and bevacizumab as second-line treatment in patients with metastatic colorectal cancer progressive during or following first-line oxaliplatin-based chemotherapy.
Authors: Yoshino Takayuki , Oki Eiji , Nozawa Hiroaki , Nakajima Takako Eguchi , Taniguchi Hiroya , Morita Satoshi , Takenaka Naruhito , Ozawa Daisuke , Shirao Kuniaki ,   The TRUSTY Study Group
Published: January 2019

TPS881 Background: Trifluridine/tipiracil is an oral combination preparation approved for the treatment of patients with metastatic colorectal cancer (mCRC). Trifluridine is a thymidine analog, and tipiracil is a thymidine phosphorylase inhibitor that improves the bioavailability of trifluridine. Phase I/II C-TASK FORCE study of trifluridine/tipiracil plus bevacizumab (Bev) for patients with refractory mCRC demonstrated a promising efficacy results with mild toxicity profile (Kuboki Y, et al. Lancet Oncology, 2017). Methods: We are conducting a randomized multicenter phase II/III non-inferiority study (JapicCTI-173618) to compare trifluridine/tipiracil plus Bev versus FOLFIRI plus Bev (in the control arm, S-1 can replace 5-FU) in second-line mCRC patients who have failed first-line oxaliplatin-based chemotherapy. Key eligibility criteria are a histologically confirmed colorectal adenocarcinoma, refractory to first-line chemotherapy including a fluoropyrimidine, oxaliplatin, and either Bev or an anti-EGFR antibody (if RAS wild-type), an age of 20 years or older, ECOG performance status of 0-1, and adequate oral intake. Patients are randomized in a 1:1 ratio to receive trifluridine/tipiracil plus Bev or FOLFIRI plus Bev using the minimization method stratified by RAS status, prior therapy (Bev/anti-EGFR antibody), and primary tumor sidedness. The primary endpoint is overall survival. The non-inferiority hypothesis will be achieved if the upper limit of the two-sided 95% CI of the HR is below 1.33 (as HR scale, power 0.80). If achieved, the non-inferiority hypothesis with the margin of 1.25 (as HR) and the superiority will be consequently tested. Secondary endpoints include progression-free survival, time to treatment failure, response rate, disease control rate, subsequent treatment, time to post-study treatment failure, the quality of life, and adverse events. The target sample size is 524 patients. Patients will be enrolled from October 2017. Clinical trial information: 173618.
Trial in progress: A phase II study of second-line FOLFIRI plus panitumumab after first-line FOLFOX plus panitumumab for RAS wild-type colorectal cancer with evaluation of circulating tumor DNA.
Authors: Maeda Hiromichi , Nagata Naoki , Nagasaka Takeshi , Oba Koji , Mishima Hideyuki , Kato Takeshi , Yoshida Kazuhiro , Muro Kei , Sakamoto Junichi 
Published: January 2019

TPS886 Background: The mechanisms underlying the acquired resistance of metastatic colorectal cancer (mCRC) against panitumumab treatment is not fully understood. The efficacy and safety of FOLFIRI with panitumumab as the second-line chemotherapy after failure of FOLFOX with panitumumab treatment has yet to be determined. To address these two points, a multicenter single-arm Phase II clinical trial is being conducted with evaluation of circulating tumor DNA (ctDNA). Methods: The major inclusion criterion is that the patient has refractory measurable tumor that has progressed after the first-line therapy with FOLFOX plus panitumumab. After registration, treatment with the FOLFIRI and panitumumab will be continued in 2-week cycles until disease progression, unacceptable toxicity and/or patients’ refusal. The primary endpoint for this study is six-month progression-free survival (PFS) rate, a simple surrogate endpoint of PFS. According to a clinical trial revealing the median PFS of 4.6 months for FOLFIRI alone and 6.4 months for panitumumab plus FOLFIRI treatment in RAS wild-type patients (Peeters et al. Clin Cancer Res. 2015; 21: 5469-79), we assume the threshold and expected 6-month PFS rate as 35% and 50%, respectively. Under the settings of one-sided alpha = 0.10 and power = 80%, the required sample size is 53 patients. The target number of cases in this study is 55 patients, considering a dropout rate of 5%. The secondary endpoint includes the tumor-related gene mutation status assessed by liquid biopsy. Primary tumor and/or metastatic site tissue samples will be collected by formalin-fixed paraffin-embedded specimens at the time of registration. Blood samples will be collected at 3 time-points: (1) before second-line treatment, (2) at 6 ± 2 weeks after initiation of the treatment protocol, and (3) after confirmation of acquired resistance to this second-line therapy. The multiple evaluation of ctDNA will provide the meaningful information concerning relationship between the tumor resistance against treatment and alterations in gene mutation status. Clinical trial information: UMIN000026817.
Blastemal progenitors modulate immune signaling during early limb regeneration
Authors: Tsai Stephanie L. , Baselga-Garriga Clara , Melton Douglas A. 
Published: January 2019

ABSTRACT
Blastema formation, a hallmark of limb regeneration, requires proliferation and migration of progenitors to the amputation plane. Although blastema formation has been well described, the transcriptional programs that drive blastemal progenitors remain unknown. We transcriptionally profiled dividing and non-dividing cells in regenerating stump tissues, as well as the wound epidermis, during early axolotl limb regeneration. Our analysis revealed unique transcriptional signatures of early dividing cells and, unexpectedly, repression of several core developmental signaling pathways in early regenerating stump tissues. We further identify an immunomodulatory role for blastemal progenitors through interleukin 8 (IL-8), a highly expressed cytokine in subpopulations of early blastemal progenitors. Ectopic il-8 expression in non-regenerating limbs induced myeloid cell recruitment, while IL-8 knockdown resulted in defective myeloid cell retention during late wound healing, delaying regeneration. Furthermore, the il-8 receptor cxcr-1/2 was expressed in myeloid cells, and inhibition of CXCR-1/2 signaling during early stages of limb regeneration prevented regeneration. Altogether, our findings suggest that blastemal progenitors are active early mediators of immune support, and identify CXCR-1/2 signaling as an important immunomodulatory pathway during the initiation of regeneration.
The cell biology of quiescent yeast – a diversity of individual scenarios
Authors: Sagot Isabelle , Laporte Damien 
Published: January 2019

ABSTRACT
Most cells, from unicellular to complex organisms, spend part of their life in quiescence, a temporary non-proliferating state. Although central for a variety of essential processes including tissue homeostasis, development and aging, quiescence is poorly understood. In fact, quiescence encompasses various cellular situations depending on the cell type and the environmental niche. Quiescent cell properties also evolve with time, adding another layer of complexity. Studying quiescence is, above all, limited by the fact that a quiescent cell can be recognized as such only after having proved that it is capable of re-proliferating. Recent cellular biology studies in yeast have reported the relocalization of hundreds of proteins and the reorganization of several cellular machineries upon proliferation cessation. These works have revealed that quiescent cells can display various properties, shedding light on a plethora of individual behaviors. The deciphering of the molecular mechanisms beyond these reorganizations, together with the understanding of their cellular functions, have begun to provide insights into the physiology of quiescent cells. In this Review, we discuss recent findings and emerging concepts in Saccharomyces cerevisiae quiescent cell biology.
Income and capital breeding in males: energetic and physiological limitations on male mating strategies
Authors: Soulsbury Carl D. 
Published: January 2019

ABSTRACT
Income and capital breeding describe two dichotomous breeding strategies that characterise the allocation of resources to reproduction. Capital breeders utilise stored endogenous resources (typically lipids) to finance reproduction, whereas income breeders use exogenous resources (typically carbohydrates). The basis for such characterisation has mainly come from studying females, yet for many species, male and female reproductive success may be determined by substantially different factors. Females allocate resources to offspring production, whereas males typically allocate resources to accessing mating opportunities, e.g. from contests or displays. The primary metabolic fuel (lipids or carbohydrates) in males appears to be dependent on the type of activity being performed (i.e. high versus low intensity or long versus short duration), rather than capital or income breeding strategy per se. Males performing sustained, long-duration effort typically utilise lipids, whereas those undergoing intense activity more often utilise carbohydrates. As a result, either fuel type can be used in either strategy. Breeding season duration can constrain strategy choice; lipids and carbohydrates can be used in short breeding season species, but only lipids provide a viable fuel source for long breeding season capital breeders. Both capital- and income-breeding males must manage their resource use during the breeding season, but capital breeders must also cope with physiological stressors associated with extended fasting. Overall, the capital–income breeding concept applies equally to male reproduction, but compared with females, there are different physical and physiological constraints that shape choice of strategy. This Commentary also highlights some key future areas that need to be investigated to further understand how capital–income breeding strategies shape male mating strategies.
Case Report: Ocular toxoplasmosis in a WHIM syndrome immunodeficiency patient
Authors: McDermott David H. , Heusinkveld Lauren E. , Zein Wadih M. , Sen H. Nida , Marquesen Martha M. , Parta Mark , Rosenzweig Sergio D. , Fahle Gary A. , Keller Michael D. , Wiley Henry E. , Murphy Philip M. 
Published: January 2019

A patient with WHIM syndrome immunodeficiency presented with sudden painless right eye blindness associated with advanced retinal and optic nerve damage. Toxoplasma gondii was detected by PCR in vitreous fluid but not serum. The patient was treated with trimethoprim-sulfamethoxazole. Vision did not return; however, the infection did not spread to involve other sites. Toxoplasmosis is rare in primary immunodeficiency disorders and is the first protozoan infection reported in WHIM syndrome.
An Approximation Algorithm for Capacity Allocation Over a Single Flight Leg with Fare-Locking
Authors: Sumida Mika , Topaloglu Huseyin 
Published: January 2019

In this paper, we study a revenue management model over a single flight leg, where the customers are allowed to lock an available fare. Each customer arrives into the system with an interest in purchasing a ticket for a particular fare class. If this fare class is available, the customer immediately purchases the ticket by paying the fare or locks the fare by paying a fee. If the customer locks the fare, then the airline reserves the capacity for the customer for a certain duration of time. At the end of this duration of time, the customer makes her ultimate purchase decision at the locked fare. The goal of the airline is to find a policy to decide which set of fare classes to make available at each time period to maximize the total expected revenue. Such fare locking options are commonly offered by airlines; the dynamic programming formulation of the revenue management problem with the option to lock an available fare has a high-dimensional state variable that keeps track of the locked fares. We develop an approximate policy that is guaranteed to obtain at least half of the optimal total expected revenue. Our approach is based on leveraging a linear programming approximation to decompose the problem by the seats on the flight and solving a dynamic program that separately controls the capacity on each seat. We also show that our results continue to hold when the airline makes pricing decisions instead of fare class availability decisions. Our numerical experiments show that the practical performance of our approximate policy is remarkably good compared to a tractable upper bound on the optimal total expected revenue. The online supplement is available at https://doi.org/10.1287/ijoc.2018.0816 .