bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation of mesothelin (MSLN) expression with future peritoneal metastases (PM) in colorectal cancer (CRC).
Authors: Malla Midhun , Rozich Noah , Hassan Ayesha , Hayat Maham , Chen Sixia , Nusrat Sanober , Goldberg Richard M. , Morris Katherine Teresa 
Published: February 2020

176 Background: CRC patients with PM have a significantly worse median overall survival (OS) when compared to those with liver and lung metastases. We studied MSLN protein expression using immunohistochemistry (IHC) on primary resected CRC (PRC), its correlation with future development of PM and its effect on OS. Our hypothesis is that PRC tumors from patients who later developed PM will have an increased proportion of positive MSLN scores based on IHC. Methods: We performed a retrospective case control study of all localized CRC (Stage I, II, III) patients who underwent curative resection from 2000- 2017 at the University of Oklahoma. The target population consisted of PRC patients who had distant recurrence during surveillance. Control group comprised of patients who never recurred after a minimum of 5 years of surveillance. MSLN score was calculated by the sum of staining percentage and intensity scores on each MSLN stained slide. Kaplan-Meier method was used to estimate OS and differences in survival were estimated using log-rank test. Results: Among 100 patients with recurrent CRC, 19 patients had PM, 51 had solid organ only metastases (SOM) and 66 are in the control group. MSLN staining results by IHC were satisfactory in 87 patients (Table). 91%, 46% and 21% of the patients in PM, SOM, and control groups had a positive MSLN score on PRC respectively. A significant association between MSLN score and future development of PM was observed (p<0.001) based on Fisher’s exact test. Sensitivity of MSLN as a marker for future PM was 93% and specificity was 58%. Patients with a positive MSLN score had a poor OS when compared to those with a negative MSLN score on univariate analysis (95% CI: 4.1-NR (not reached), p <0.001), which lost significance on multi-variable cox proportional analyses. Conclusions: A higher proportion of patients in the PM group had a positive MSLN score on PRC when compared to the SOM and control groups. MSLN was found to be a highly sensitive marker for future PM in CRC. We intend to expand this work by examining an additional cohort to validate these findings. [Table: see text]
Potency of CD8+ T-cell mediated antitumor immunity from intratumoral immunotherapy with STING agonist, ADU-S100, in an esophageal adenocarcinoma model.
Authors: Babar Laila , Zaidi Ali Hussainy , Kelly Ronan Joseph , Omstead Ashten N. , Zheng Ping , Kosovec Juliann E. , Ayazi Shahin , Finley Gene Grant , Jobe Blair Anderson , Goel Ajay , Gorbunova Anastasia , Salvitti Madison 
Published: February 2020

408 Background: Esophageal adenocarcinoma (EAC) is a deadly disease with poor prognosis due to limited treatment options. STING is a transmembrane protein that activates the transcription of type I IFN genes, resulting in the stimulation of APCs and enhanced CD8+ T-cell infiltration. Recently, STING agonists have demonstrated durable anticancer activity in solid tumors when used alone and in combination with either chemotherapy, radiation or immunotherapy. In this study we evaluated the efficacy and immunomodulatory effects of STING agonist +/- radiation in an established EAC model. Methods: Esophagojejunostomy was performed on rats to induce reflux leading to the development EAC. At 32 weeks post operatively, rats received either STING (ADU-S100) or placebo (PBS), +/- 16Gy radiation. Drug efficacy was evaluated by pre- and post- treatment MRI, serial biopsies, histology and RT-PCR. Additionally, immunofluorescence was performed using CD8 and PD-L1 antibodies. Results: A comparison of MRIs in the study groups between 32 and 40 weeks demonstrated a mean increase in percentage tumor volume of 76.7 % and 152.4% in the P and P+R arms and a decrease of 30.1 % and 50.8% in the S and S+R arms, respectively (ANOVA test p < 0.0001) Overall, the S+R group demonstrated the best results with maximum mean volume reduction with all cases responding. Downstream gene expression, pre, on, and post- treatment demonstrated significant upregulation of IFNβ, TNFα, IL-6 and CCL-2 in the treatment groups compared with placebo. On and post treatment, radiation alone, ADU-S100 alone and ADU-S100 + radiation groups demonstrated enhanced PD-LI expression, induced by higher densities of IFNγ producing CD8+ T-cells (p < 0.01). Conclusions: ADU-S100 +/- radiation exhibits potent anti-tumor efficacy and a promising immunomodulatory profile in a de novo EAC model providing the rationale for clinical testing, likely concurrently in combination with immune checkpoint inhibitors.
Eligibility for second-line therapy in patients with advanced hepatocellular carcinoma (aHCC): A BC Cancer population-based study.
Authors: Tsang Erica S. , Davies Janine Marie , Loree Jonathan M. , Lim Howard John , Renouf Daniel John , Gill Sharlene 
Published: February 2020

491 Background: Evidence supporting second-line therapies has become available for aHCC, including regorafenib, cabozantinib, ramucirumab, and nivolumab. The optimal second-line treatment regimen is unknown, and there remains limited real-world data about the eligibility of patients for second-line therapies in aHCC. We aimed to characterize the real-world eligibility and use of second-line therapies post sorafenib. Methods: We identified all patients with aHCC who received ≥1 cycle of first-line sorafenib between January 1, 2014 and December 31, 2017 across 6 centers in British Columbia (BC), Canada. All patients were required to be Child-Pugh class A for initiation of sorafenib in BC. Baseline characteristics and clinical outcomes were reviewed. Eligibility for second-line therapy was determined using the RESORCE and CELESTIAL study entry criteria. Results: Of 144 patients with advanced HCC who received ≥1 cycle of first-line sorafenib, median age was 65.3 years (range 32.2-83.4) and 85% were male. Median duration of sorafenib was 2.6 months. 12 patients (8%) went on to receive second-line treatment. 37 patients (26%) were deemed eligible for second-line systemic therapy. Primary reasons for ineligibility included ECOG ≥2 (58%), and deterioration to Child-Pugh status B (28%). On Cox regression, improved survival was associated with better ECOG and recurrent disease. (Table). Kaplan-Meier analysis demonstrated that eligibility for second-line treatment was associated with improved median overall survival from end of first-line treatment (8.5 vs. 5.1 months; p<0.01). Conclusions: Only a minority of real-world patients with aHCC were eligible for second-line therapies based on second-line trial criteria. Given the high-rate of attrition, improved first-line treatment options are urgently needed. [Table: see text]
Subsequent anticancer procedures following first-line lenvatinib (LEN): A post hoc analysis from the phase III REFLECT study in unresectable hepatocellular carcinoma (uHCC).
Authors: Alsina Angel , Kudo Masatoshi , Vogel Arndt , Cheng Ann-Lii , Tak Won Young , Ryoo Baek-Yeol , Evans T.R. Jeffry , Lopéz Lopéz Carlos , Daniele Bruno , Blanc Jean-Frédéric , Ren Min , Baldwin Rae Lynn , Izumi Namiki , Qin Shukui , Finn Richard S. 
Published: February 2020

520 Background: The availability of newer therapeutic options has shifted the treatment paradigm for uHCC, evoking questions regarding the sequencing of anticancer therapies. REFLECT was a phase 3 study comparing the efficacy and safety of LEN versus sorafenib (SOR) in first-line treatment of patients (pts) who have uHCC. In this post hoc analysis, we investigated overall survival (OS) during the follow-up survival period between treatment arms for pts who did and did not receive subsequent anticancer procedures and for responders to first-line LEN who received subsequent anticancer procedures. Methods: Pts in REFLECT were randomized 1:1 to LEN or SOR. The follow-up period commenced at the first visit after stopping study medications. Pts were followed-up every 12 weeks until data cutoff (Nov 13, 2016) or death. OS was estimated using the Kaplan–Meier method and presented with a 95% confidence interval (CI). Pts receiving subsequent radiotherapy were excluded from the OS analysis. Results: Of the 954 pts enrolled in REFLECT, 122/478 (26%) LEN- and 130/476 (27%) SOR-treated pts received subsequent anticancer procedures, with the most common being transarterial chemotherapy embolization (LEN n = 69 [14.4%]; SOR n = 81 [17.0%]) and hepatic intra-arterial chemotherapy (LEN n = 23 [4.8%]; SOR n = 25 [5.3%]). Eastern Cooperative Oncology Group performance status scores and laboratory assessments, including liver function, were comparable between arms at first-line treatment discontinuation. Of the pts who received subsequent anticancer procedures, those randomized to first-line LEN (n = 99) had a longer median OS (23.0 vs 19.6 months, respectively; hazard ratio [HR]: 0.71; 95% CI: 0.51–1.01) than those randomized to first-line SOR (n = 112). Responders to first-line LEN who received subsequent anticancer procedures (n = 45) had a median OS of 27.2 months (95% CI: 20.7–29.8). There were too few SOR responders (n = 10) who received subsequent anticancer procedures to evaluate OS. Conclusions: Pts randomized to first-line LEN who received subsequent anticancer procedures had longer OS compared with the similar sequence for pts taking first-line SOR. Clinical trial information: NCT01761266.
A pilot study of durvalumab/tremelimumab (durva/treme) and radiation (XRT) for metastatic biliary tract cancer (mBTC): Preliminary safety and efficacy.
Authors: Hong Theodore S. , Goyal Lipika , Parikh Aparna Raj , Yeap Beow Y. , Ulysse Christine A. , Drapek Lorraine C. , Allen Jill N. , Clark Jeffrey William , Christopher Benjamin , Bolton Christine , Ryan David P. , Corcoran Ryan Bruce , Meyerhardt Jeffrey A. , Wo Jennifer Yon-Li , Zhu Andrew X. 
Published: February 2020

547 Background: Metastatic biliary tract cancer (mBTC) is a lethal malignancy with median 5 year OS of less than 10%. Immunotherapy, particularly single agent anti-PD-1/PD-L1, has limited efficacy in mBTC with ORR~9-15%. Recently presented data shows responses in metastatic MSS pancreatic or colon cancer with combination anti-PD-1/CTLA-4 and radiation (XRT) to produce systemic response (abscopal effect) (Parikh A, GI ASCO 2019, ASCO 2019.). We evaluate safety and efficacy of dual PD-1/CTLA-4 inhibition with XRT in MSS mBTC. Methods: 15 of a planned 15 mBTC patients were enrolled. Eligible pts had histologically-confirmed mBTC, ECOG-PS 0/1, and must have progressed on at least one line of previous therapy or refused standard therapy. Safety cohort of 6 pts of durva 1500 mg/treme 75 mg q4w was enrolled. If > 2 DLTs, patients were enrolled subsequently to dose level -1 (durva 1125 mg/ treme 75 mg q4w). 3 fractions of 8 Gy of radiation at C2D1 every other day to a single metastatic site. Durva/treme continued for 4 cycles, followed by 4 cycles of maintenance durva until progressive disease, discontinuation or withdrawal. Endpoints include disease control rate (DCR (SD+PR+CR)), PFS and OS and safety. Radiological evaluations were done q2 mo. Results: 15 mBTC pts enrolled and evaluable from May 2018 to March 2019. Median age 63 years (range 48-75), 47% male. DLTs occurred in 3 patients during the safety run-in. One patient experienced DLT at dose level -1 and subsequent expansion. 3 patients did NOT reach radiation therapy. DCR was 27% with a 13% PR and 7% CR. Of those who reached radiation, DCR was 33% with a 17% PR and 8% CR. At time of analysis, median PFS was 54 days for ITT mBTC. Duration of response for 4 patients with DCR was 26, 52, 122, 254+ days. Treatment-related adverse events were reported in 12/15 patients (80%). Grade ≥3 toxicities were seen in 9/15 pts (60%) with lymphopenia (5 grade 3) and elevated LFTs (2 grade 4 and 4 grade 2) being the main adverse events. All patients with disease control were not MSI. Conclusions: Combination of durva/treme XRT is feasible and shows preliminary activity in metastatic BTC. An expansion cohort is being planned to confirm activity. Clinical trial information: NCT03482102.
Phase Ib/II open-label, randomized evaluation of 2L atezolizumab (atezo) + BL-8040 versus control in MORPHEUS-pancreatic ductal adenocarcinoma (M-PDAC) and MORPHEUS-gastric cancer (M-GC).
Authors: Oh Do-Youn , Ajani Jaffer A. , Bang Yung-Jue , Chung Hyun Cheol , Lacy Jill , Lee Jeeyun , Macarulla Teresa , Manji Gulam Abbas , O'Reilly Eileen Mary , Allen Simon , Al-Sakaff Nedal Jaffer Abdulla , Barak Hila , Patel Jilpa , Pintoffl Jan Peter , Shemesh Colby , Zhang Wei , Zhang Xiaosong , Chau Ian 
Published: February 2020

712 Background: The MORPHEUS platform comprises multiple Ph Ib/II trials to identify early efficacy signals and safety of treatment (tx) combinations across cancers. Due to the immune-mediated effects of BL-8040, a high-affinity antagonist for CXCR4, it was tested with atezo (anti-PD-L1) in pts with advanced/metastatic (m) PDAC and GC. Methods: In 2 separate randomized trials, pts with mPDAC or advanced/mGC who progressed on 1L chemo received either atezo + BL-8040 (BL-8040 1.25 mg/kg SC D1-5, then BL-8040 1.25 mg/kg SC TIW + atezo 1200 mg IV Q3W) or control tx (M-PDAC: mFOLFOX-6 or gemcitabine + nab-paclitaxel; M-GC: paclitaxel + ramucirumab). Primary endpoints were investigator-assessed ORR per RECIST 1.1 and safety. Results: Efficacy from evaluable pts followed for ≥18 wks in M-PDAC and ≥8 wks in M-GC is summarized in the table; 24-wk M-GC data will be presented. There were 15 safety-evaluable pts in each M-PDAC arm, as well as 13 in the atezo + BL-8040 and 12 in the control arm of M-GC. Gr 3-5 AEs were seen in 47% of pts on atezo + BL-8040 and 67% on control in M-PDAC, and 77% on atezo + BL-8040 and 67% on control in M-GC. Tx-related SAEs in M-PDAC occurred in 7% of pts on atezo + BL-8040 and 20% on control, and in M-GC, in 8% of pts on control. No Gr 5 AEs occurred in atezo + BL-8040 arms. Tx-related AEs led to 7% and 8% of pts discontinuing tx in the M-PDAC and M-GC control arms, respectively, and 15% discontinuing BL-8040 in M-GC due to Gr 3 injection-related reactions. Biomarker and PK data will be presented. Conclusions: Atezo + BL-8040 had limited efficacy for PDAC or GC. Tx-related AEs with atezo + BL-8040 were consistent with each agent’s known safety profile. Clinical trial information: NCT03281369; NCT03193190 . [Table: see text]
Hyperactive LH Pulses and Elevated Kisspeptin and NKB Gene Expression in the Arcuate Nucleus of a PCOS Mouse Model
Authors: Esparza Lourdes A , Schafer Danielle , Ho Brian S , Thackray Varykina G , Kauffman Alexander S 
Published: February 2020

Abstract
Polycystic ovary syndrome (PCOS), a common reproductive disorder in women, is characterized by hyperandrogenemia, chronic anovulation, cystic ovarian follicles, and luteinizing hormone (LH) hyper-pulsatility, but the pathophysiology isn’t completely understood. We recently reported a novel mouse model of PCOS using chronic letrozole (LET; aromatase inhibitor). Letrozole-treated females demonstrate multiple PCOS-like phenotypes, including polycystic ovaries, anovulation, and elevated circulating testosterone and LH, assayed in “one-off” measures. However, due to technical limitations, in vivo LH pulsatile secretion, which is elevated in PCOS women, was not previously studied, nor were the possible changes in reproductive neurons. Here, we used recent technical advances to examine in vivo LH pulse dynamics of freely moving LET female mice versus control and ovariectomized (OVX) mice. We also determined whether neural gene expression of important reproductive regulators such as kisspeptin, neurokinin B (NKB), and dynorphin, is altered in LET females. Compared to controls, LET females exhibited very rapid, elevated in vivo LH pulsatility, with increased pulse frequency, amplitude, and basal levels, similar to PCOS women. Letrozole-treated mice also had markedly elevated Kiss1, Tac2, and Pdyn expression and increased Kiss1 neuronal activation in the hypothalamic arcuate nucleus. Notably, the hyperactive LH pulses and increased kisspeptin neuron measures of LET mice were not as elevated as OVX females. Our findings indicate that LET mice, like PCOS women, have markedly elevated LH pulsatility, which likely drives increased androgen secretion. Increased hypothalamic kisspeptin and NKB levels may be fundamental contributors to the hyperactive LH pulse secretion in the LET PCOS-like condition and, perhaps, in PCOS women.
Recent advances in functional genomics for parasitic nematodes of mammals
Authors: Castelletto Michelle L. , Gang Spencer S. , Hallem Elissa A. 
Published: February 2020

ABSTRACTHuman-parasitic nematodes infect over a quarter of the world's population and are a major cause of morbidity in low-resource settings. Currently available treatments have not been sufficient to eliminate infections in endemic areas, and drug resistance is an increasing concern, making new treatment options a priority. The development of new treatments requires an improved understanding of the basic biology of these nematodes. Specifically, a better understanding of parasitic nematode development, reproduction and behavior may yield novel drug targets or new opportunities for intervention such as repellents or traps. Until recently, our ability to study parasitic nematode biology was limited because few tools were available for their genetic manipulation. This is now changing as a result of recent advances in the large-scale sequencing of nematode genomes and the development of new techniques for their genetic manipulation. Notably, skin-penetrating gastrointestinal nematodes in the genus Strongyloides are now amenable to transgenesis, RNAi and CRISPR/Cas9-mediated targeted mutagenesis, positioning the Strongyloides species as model parasitic nematode systems. A number of other mammalian-parasitic nematodes, including the giant roundworm Ascaris suum and the tissue-dwelling filarial nematode Brugia malayi, are also now amenable to transgenesis and/or RNAi in some contexts. Using these tools, recent studies of Strongyloides species have already provided insight into the molecular pathways that control the developmental decision to form infective larvae and that drive the host-seeking behaviors of infective larvae. Ultimately, a mechanistic understanding of these processes could lead to the development of new avenues for nematode control.
Evolution, developmental expression and function of odorant receptors in insects
Authors: Yan Hua , Jafari Shadi , Pask Gregory , Zhou Xiaofan , Reinberg Danny , Desplan Claude 
Published: February 2020

ABSTRACT
Animals rely on their chemosensory system to discriminate among a very large number of attractive or repulsive chemical cues in the environment, which is essential to respond with proper action. The olfactory sensory systems in insects share significant similarities with those of vertebrates, although they also exhibit dramatic differences, such as the molecular nature of the odorant receptors (ORs): insect ORs function as heteromeric ion channels with a common Orco subunit, unlike the G-protein-coupled olfactory receptors found in vertebrates. Remarkable progress has recently been made in understanding the evolution, development and function of insect odorant receptor neurons (ORNs). These studies have uncovered the diversity of olfactory sensory systems among insect species, including in eusocial insects that rely extensively on olfactory sensing of pheromones for social communication. However, further studies, notably functional analyses, are needed to improve our understanding of the origins of the Orco–OR system, the mechanisms of ORN fate determination, and the extraordinary diversity of behavioral responses to chemical cues.
How to turn an organism into a model organism in 10 ‘easy’ steps
Authors: Matthews Benjamin J. , Vosshall Leslie B. 
Published: February 2020

ABSTRACT
Many of the major biological discoveries of the 20th century were made using just six species: Escherichia coli bacteria, Saccharomyces cerevisiae and Schizosaccharomyces pombe yeast, Caenorhabditis elegans nematodes, Drosophila melanogaster flies and Mus musculus mice. Our molecular understanding of the cell division cycle, embryonic development, biological clocks and metabolism were all obtained through genetic analysis using these species. Yet the ‘big 6’ did not start out as genetic model organisms (hereafter ‘model organisms’), so how did they mature into such powerful systems? First, these model organisms are abundant human commensals: they are the bacteria in our gut, the yeast in our beer and bread, the nematodes in our compost pile, the flies in our kitchen and the mice in our walls. Because of this, they are cheaply, easily and rapidly bred in the laboratory and in addition were amenable to genetic analysis. How and why should we add additional species to this roster? We argue that specialist species will reveal new secrets in important areas of biology and that with modern technological innovations like next-generation sequencing and CRISPR-Cas9 genome editing, the time is ripe to move beyond the big 6. In this review, we chart a 10-step path to this goal, using our own experience with the Aedes aegypti mosquito, which we built into a model organism for neurobiology in one decade. Insights into the biology of this deadly disease vector require that we work with the mosquito itself rather than modeling its biology in another species.
Current Concepts in Brain Tumor Imaging
Authors: Norden Andrew D. , Pope Whitney B. , Chang Susan M. 
Published: February 2020

Overview: Magnetic resonance imaging (MRI) is the most useful imaging tool in the evaluation of patients with brain tumors. Most information is supplied by standard anatomic images that were developed in the 1980s and 1990s. More recently, functional imaging including diffusion and perfusion MRI has been investigated as a way to generate predictive and prognostic biomarkers for high-grade glioma evaluation, but additional research is needed to establish the added benefits of these indices to standard MRI. Response critieria for high-grade gliomas have recently been updated by the Response Assessment in Neuro-Oncology (RANO) working group. The new criteria account for nonenhancing tumor in addition to the contrast-enhancing abnormalities on which older criteria relied. This issue has recently come to the fore with the introduction of the antiangiogenic agent bevacizumab into standard treatment for recurrent glioblastoma. Because of its potent antipermeability effect, contrast enhancement is markedly reduced in patients who receive bevacizumab. The RANO criteria also address the phenomenon of pseudoprogression, in which there may be transient MRI worsening of a glioblastoma following concurrent radiotherapy and temozolomide.
Reducing the Cost of Cancer Care: How to Bend the Curve Downward
Authors: Smith Thomas J. , Hillner Bruce E. , Kelly Ronan J. 
Published: February 2020

Overview: Health care and cancer care costs are rising unsustainably such that insurance costs have doubled in 10 years. Oncologists find themselves both victims of high costs and the cause of high-cost care by what we do and what we do not do. We previously outlined five ways that oncologists could personally bend the cost curve downward and five societal attitudes that would require change to lower costs. Here, we present some practical ways to reduce costs while maintaining or improving quality, including: 1) evidence-based surveillance after curative therapy; 2) reduced use of white cell stimulating factors (filgrastim and pegfilgrastim); 3) better integration of palliative care into usual oncology care; and 4) use of evidence-based, cost-conscious clinical pathways that allow appropriate care and lead to equal or better outcomes at one-third lower cost.