tbuckley/cabot-search huggingface dataset:
Placebo-controlled phase III study comparing dexamethasone on day 1 to on day 1-3 with NK<sub>1</sub> receptor antagonist and palonosetoron in high emetogenic chemotherapy.
Authors: Kunihiro Matsuzaki, Yuka Ito, Mamoru Fukuda, Kentaro Sakamaki, Masahiko Ando, Yasuyuki Kojima, Naoki Furuya, Takashi Tsuda, Hiroko Minatogawa, Yasushi Ichikawa, Ichiro Ohta, Saori Takei, Yutaka Tokuda, Kazutaka Narui, Ayako Tsuboya, Takashi Suda, Satoshi Morita, Takeharu Yamanaka, Narikazu Boku, Takako Eguchi Nakajima
Journal: Journal of Clinical Oncology (2016)

10019 Background: Standard antiemetic therapy for chemotherapy-induced nausea and vomiting in high emetogenic chemotherapy (HEC) is a combination of NK1 receptor antagonist, 5-HT3 receptor antagonist and dexamethasone (DEX) on day 1-3. This study compared the efficacy of DEX on day 1 to on day 1-3 due to reduce side effects of DEX. Methods: Patients with a malignant solid tumor to receive HEC (containing > 50 mg/m2 of cisplatin or anthracycline+cyclophosphamide) were randomly assigned to Arm A (DEX on day 1-3) or Arm B (DEX on day 1) with NK1 receptor antagonist and palonosetron. Primary endpoint was complete response (CR) rate defined as no emetic episodes and no rescue medications in the overall (0-120h) phase. Secondary endpoints included CR rates in the acute (0-24h) and delayed (24-120h) phases, severity of nausea, adverse events (AEs) related to DEX and chemotherapy with CTCAE ver 4.0 on day 1-5, and quality of life with EROTC QLQ-C30 on day 5. The planned sample size of 400 provided power of 80% to detect the non-inferiority of Arm B to Arm A with the non-inferiority margin of difference by 15% in CR rate (one-sided α=0.025). Results: 401pts were enrolled and 396 pts were evaluable. Baseline characteristics were well-balanced. CR rates in the overall phase were 46.9% in Arm A and 44.0% in Arm B (risk difference: -2.9%, 95%CI: -12.6%-6.8%, P=0.007 for non-inferiority). CR rates in Arm A and in Arm B were 63.3% and 64.5% (risk difference: 1.2%, 95% CI: -8.1%-10.6%, P<0.001) in the acute phase; 56.6% and 51.5% (risk difference: -5.1%, 95% CI: -14.8%-4.6%, P=0.023) in the delayed phase, respectively. The severity of nausea was not significantly different between 2 arms on each day. AEs related to DEX depends on the duration of DEX administration: hot flushes on day 4 (P=0.013) and 5 (P=0.038) and tremor on day 5 (P=0.041) were observed more frequently in Arm A, while anorexia on day 2 (P=0.039) and 3 (P=0.006), depression on day 2 (P=0.045) and fatigue on day 2 (P=0.001) and 3 (P=0.004) were more in Arm B. Other grade >3 AEs and Global health status in QOL were similar between 2 arms. Conclusions: Administration of DEX can be limited to on day 1 in anti-emetic therapy for HEC. Clinical trial information: UMIN000008867.
Abstract 14581: Occlusion of Left Anterior Descending Artery Impairs Microvascular Function in the Left Circumflex and the Right Coronary Artery Area in Adult Porcine
Authors: Shin Yajima, Shigeru Miyagawa, Satsuki Fukushima, Yoshiki Sawa
Journal: Circulation (2016)

Introduction: Occlusion of major coronary artery induces myocardial infarction (MI) leading to remodeling of the left ventricle (LV), which is reportedly caused by progressive dysfunction of the microvasculature. Hypothesis: We herein hypothesized occlusion of the major coronary artery may induce microvascular dysfunction in the adjacent area which is perfused by the intact coronary arteries. Methods: MI was induced by the placement of the ameroid constrictor ring around the left anterior descending artery (LAD) in adult Gottingen pigs 8 weeks before the assessment, while age-matched normal ones were used for the control (n=6 each). Regional wall motion, myocardial blood flow (MBF) and index of microvascular resistance (IMR) of the LV was studied by cardiac magnetic resonance (CMR), 13N-ammonia positron emission tomogram (PET) and fluoroscopy-guided pressure wire studies, respectively. Results: The CMR study consistently showed akinetic anterior LV wall with an ejection fraction of 40±7% at 4 weeks and 40...
Detecting T790M mutation of tissue and plasma ctDNA samples by ARMS in <i>EGFR</i>-mutant NSCLC patients after disease progression.
Authors: Ya-Lan Wu, Rui-Zhan Tong, Yan Zhang, Bin-Bin Hu, Ke Zhen, Qian Zhao, Xiao-Juan Zhou, Zhen-Yu Ding, Feng Peng, You-Ling Gong, Yong Xu, Jin Wang, Li Ren, Yong-Mei Liu, You Lu
Journal: Journal of Clinical Oncology (2017)

e20625 Background: T790M mutation is the most common mechanism of acquired EGFR TKI resistance. The use of T790M-targeted EGFR TKIs needs re-biopsy to confirm the existence of sensitive mutation. People wonder whether blood can replace tissue to diagnose acquired T790M mutation. Methods: We performed a prospective study in our institution (West China Hospital, Chengdu, China) between 2014 and 2016. Patients were eligible if they have advanced EGFR-mutant NSCLC, clinical resistance to EGFR TKIs, and were undergoing a re-biopsy for EGFR genotyping as part of their routine clinical care. We used ARMS to sequence EGFR of tissue and blood sample. Blood collection was performed within 2 weeks of the repeat biopsy. Measurement of diagnostic concordance among two different methods was done using cohen’s kappa, and the McNemar test used to judge significance. All statistical analysis was performed with the use of SPSS 20.0. Results: Forty-five patients were enrolled in this study. Thirty-eight patients received tissue test, thirty-one patients received plasma ctDNA test, and twenty-four patients received both tissue and plasma ctDNA tests. 26/38 (38.4%) reported positive T790M mutation by tissue test, and 13/31 (41.9%) by plasma ctDNA test. In 24 patients received both tissue and plasma ctDNA tests, 10/24 (41.7%) were concordant for T790M mutation status (κ = 0.006, p = 0.013). The positive rate of T790M mutation is 70.8% by tissue test, and 37.5% by plasma ctDNA test. In 17 patients reported positive T790M mutation by tissue test, 7/17 (41.2%) also reported positive T790M mutation by plasma ctDNA test, and 3 of the 7 positive ctDNA tests (42.9%) reported weakly positive T790M mutation. In the other 7 patients reported negative T790M mutation by tissue test, 2/7 (28.6%) reported positive T790M mutation by plasma ctDNA test. Conclusions: The positive rate of ARMS in our study is high than that of some reported new technologies. The level of plasma ctDNA was reported to relate to prognosis. Hence, plasma ctDNA cannot fully replace tissue to diagnose acquired T790M mutation after disease progression. It is important and significant to develop new technology to improve the safety of tissue biopsy.
Age-related real-world outcomes for patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Melissa Curtis, Nathan Coleman Nussbaum, Harvey J. Hamrick, Caroline Savage Bennette, Neal J. Meropol, Rebecca A. Miksad
Journal: Journal of Clinical Oncology (2018)

3613 Background: There are scant data regarding the diagnosis, treatment, and outcomes for mCRC pts diagnosed at a very young age ( < 30 yrs). We therefore explored age-related pt and tumor characteristics, treatment patterns and OS among mCRC pts treated in routine clinical practice. Methods: We retrospectively analyzed a national sample of pts ≥18 yrs old with confirmed mCRC diagnosed on or after 01/1/2014 (N = 10,990) using the Flatiron Health database. Descriptive statistics summarized pt and tumor characteristics and treatment patterns. Overall survival (OS) was indexed to mCRC diagnosis date. OS curves were estimated with Kaplan-Meier method. P-values were calculated for trend across all age groups. Results: Pt characteristics, mutation testing and 1st-line (1L) therapy trends differed significantly across age groups (results for < 30 and > 70 yrs age groups in Table). Median OS significantly differed by age, with a peak for those 40-49 yrs at diagnosis: 21.8 mos ( < 30 yrs), 21.0 mos (30-39 yrs), 27.5 mos (40-49 yrs), 26.5 mos (50-59 yrs), 22.3 mos (60-69 yrs), 15.8 mos ( > 70 yrs), p-value < 0.0001. Conclusions: 1L treatment and OS for mCRC pts differed significantly by age at diagnosis in unadjusted analysis. Despite more often receiving 1L aggressive therapy (FOLFOX/FOLFIRI/FOLFOXIRI +/- ab), younger age groups had worse OS compared to all other age groups except > 70 yrs. Over-representation (compared to US 2010 census) of young African Americans supports earlier screening. Documentation of standard mutational testing significantly differed by age, and mutation positivity differed for BRAF. These findings suggest that a complex interplay between biologic, diagnostic and treatment factors may affect age- and race-based disparities in mCRC outcomes. Age group (yrs) p-value (across all age groups) < 30 (%) N = 62 > 70 (%) N = 4339 Stage 4 at diagnosis 77.4 50.8 < 0.001 African American 19.6 9 < 0.001 Mutation Tested BRAF 54.8 26.2 < 0.001 positive 11.8 16.5 < 0.001 KRAS 75.8 57.7 < 0.001 positive 40.4 40.5 0.3 NRAS 50.0 27.6 < 0.001 positive 0 4.6 0.5 1L regimen FOLFOX/FOLFIRI 14.5 12.8 < 0.001 FOLFOX/FOLFIRI + antibody (ab) 50 29.7 FOLFOXIRI +/- ab 8.1 0.3 Other 11.3 31.5 None 16.1 25.7
P01.035 Nivolumab and Temozolomide (TMZ) vs TMZ alone in newly diagnosed elderly patients (pts) with Glioblastoma (GBM) (NUTMEG): Trial in progress
Authors: M Khasraw, K McDonald, S Yip, R G Verhaak, A B Heimberger, M Hall, E Barnes, E Hovey, B M Ellingson, Z Lwin
Journal: Neuro-Oncology (2018)

TMZ with short course radiotherapy (RT) is an option for elderly GBM patients. Nivolumab is a PD-1 inhibitor with known safety profile in GBM. An increase of mutations as we age is well documented in GBM and in cancer in general. A higher mutational load is associated with increased response to nivolumab. NUTMEG examines activity of nivolumab added to TMZ in GBM patients 65 years or older. NUTMEG patients will receive RT (40Gy/15 fractions) concurrently with TMZ 75mg/m2. Post-radiation, the experimental group will receive nivolumab (240 mg days 1 and 15 Q 28 days for cycles 1–4; then 480 mg day 1 Q 28 days for cycles 5–6) with adjuvant TMZ (150-200mg/m2 days 1–5 Q 28 days) for 6 cycles. The standard treatment group will receive same dose and schedule of TMZ. The primary endpoint is Overall Survival (OS). Secondary endpoints include: 6-month (mo) Progression Free Survival (PFS-6), adverse events using NCI CTCAE v4.03 incorporating immune related AEs, QoL (EORTC QLQ-30, BN-20, and EuroQol EQ-5D-5L), Neurologic Assessment in Neuro-Oncology (NANO) Scale and correlation between modified RANO and immune-related RANO in the experimental arm. Translational research (TR) endpoints include mutational burden deciphered by whole exome sequencing; immune-related markers PD-L1, CD3+, CD4+, CD8+ and FOXP3 tumour infiltrating lymphocytes (TILs) and correlation with clinical outcomes. Advanced MRI will assess distribution of perfusion and diffusion, 3D morphometric and texture features and pH-weighted imaging correlated with clinical and TR endpoints. Safety will be reviewed by an independent data safety monitoring committee. Assuming a median OS of 9 mo, and accrual of 18mo and ≥24 mo follow-up 102 patients will be randomized in a 2:1 allocation (68 in the experimental arm and 34 in the control arm). This randomized phase II design targets a hazard ratio (HR) TMZ + nivolumab: TMZ for survival between experimental and control arms with a 90% CI of HR/1.46 to HR*1.46. If the upper limit is less than 1, we would conclude TMZ + nivolumab to be superior to warrant further investigation. This phase II design may be converted to a larger phase III trial if, at the end of the study, the number of events is sufficiently large. At 28 May 2018, 5/18 study sites are open in Australia with 5 patients randomized. ACTRN12617000267358. Supported by NHMRC Project grant APP1125204 and Bristol-Myers Squibb.
Incretin based drugs and the risk of cholangiocarcinoma in patients with type 2 diabetes.
Authors: Devin Abrahami, Antonios Douros, Hui Yin, Nathaniel Bouganim, Oriana Yu, Jean-Luc Faillie, Robert Platt, Laurent Azoulay
Journal: Journal of Clinical Oncology (2018)

e16126 Background: Dipeptidyl peptidase-4 inhibitors (DPP4Is) and glucagon-like peptide-1 receptor agonists (GLP1 RAs) are commonly prescribed antidiabetic drugs. However, there is some evidence that they may increase the risk of cholangiocarcinoma (CCA). This study was the first observational study conducted to determine whether use of DPP4Is and GLP1 RAs is associated with an increased risk of CCA in patients with type 2 diabetes. Methods: Using the UK Clinical Practice Research Datalink, we identified a cohort of 149,730 patients newly treated with antidiabetic drugs between January 1, 2007 and June 30, 2016. Time dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of incident CCA associated with use of DPP4Is and GLP1 RAs, separately, when compared with use of at least two antidiabetic drug classes, with exposures lagged by one year for latency. Secondary analyses assessed whether the association varied by cumulative duration of use and time since initiation. Models were adjusted for age, sex, smoking status, BMI, alcohol related disorders, markers of diabetes severity, and comorbidity. Sensitivity analyses were conducted to assess robustness. Results: During 572,848 person years of follow up, there were 85 incident CCA events (incidence rate: 14.8/100,000/year). Use of DPP4Is was associated with an over two fold increased hazard of CCA, when compared with use of at least two antidiabetic drug classes (23.8 vs 12.1/100,000/year, respectively; HR: 2.14, 95% CI: 1.18-3.87). HRs increased with longer durations of use, reaching a peak after one to two years of use (HR: 2.66, 95% CI: 1.22-5.79), and decreasing thereafter (HR: 1.42, 95% CI: 0.57-3.57). A similar pattern was observed with time since initiation. Use of GLP-1 RAs generated an elevated association with a wide confidence interval (HR: 2.20, 95% CI: 0.81-6.02). A low number of GLP1 RA exposed events precluded from assessing duration-response relationships. These findings remained consistent in sensitivity analyses. Conclusions: The results of this population-based study indicate that use of DPP4Is, and possibly GLP1 RAs, may be associated with an increased risk of CCA in patients with type 2 diabetes.
OP0223 Targeting chondrocyte plasticity via connexin43 modulation attenuates cellular senescence in osteoarthritis
Authors: M. Varela-Eirín, A. Varela-Vázquez, C. Paíno, A. Casado-Díaz, J.M. Quesada-Gómez, E. Fonseca, T. Aasen, A. Tabernero, J.R. Caeiro, A. Blanco, M.D. Mayán
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Chondrocytes in articular cartilage undergo phenotypic changes and senescence, restricting cartilage regeneration and favouring the osteoarthritis (OA) progression, a chronic disease characterised by degeneration of articular cartilage leading to physical disability and pain. Like other wound healing disorders, chondrocytes from OA patients show a chronic increase in the transmembrane channel protein connexin43 (Cx43), which through the exchange of factors or recruitment/release of signalling factors to the membrane regulates signal transduction. Immature or stem-like cells are found in cartilage isolated from OA patients, yet their origin and role in disease progression are unknown. <h3>Objectives</h3> Our objective was to investigate the role of Cx43 in chondrocyte plasticity during osteoarthritis. <h3>Methods</h3> Human mesenchymal stem cells and chondrocytes from osteoarthritic donors were used in this study. Protein levels were evaluated by western blot, immunofluorescence and flow cytometry. RNA expression was evaluated by RT-qPCR. Cell communication was studied by scrape loading assay and flow cytometry. <h3>Results</h3> Here we show that Cx43 acts as a positive regulator of the reversion of human chondrocytes to a less differentiated state. Overactivity of Cx43 in the membrane largely maintain this stem-like phenotype by increasing the basic helix–loop–helix transcription factor TWIST-1 and tissue remodelling and proinflammatory factors such as MMPs and IL-6, which in turn lead to cellular senescence by upregulation of p53 and p16INK4a, contributing to the senescence-associated secretory phenotype (SASP). Downregulation of Cx43 leads to redifferentiation of osteoarthritic chondrocytes (OAc) into more differentiated state decreasing MMPs, proinflammatory cytokines production and cellular senescence. Collectively, these results identify a causal Cx43-sensitive circuit in chondrocytes that regulates dedifferentiation and redifferentiation events involved in wound healing and tissue repair. In addition we show that chronic dedifferentiation drives catabolic processes and cellular senescence. <h3>Conclusions</h3> Targeting Cx43 allows dedifferentiated chondrocytes to revert to a chondrocyte-specific phenotype and its subsequent recovery in a predictable manner. These findings support the use of Cx43 as an appropriate therapeutic target to halt OA progression and to promote cartilage regeneration <h3>Disclosure of Interest</h3> None declared
AB0499 Evaluation of the effectiveness of metaxodine in the hepatic toxicity due to methotrexate in patients with rheumatoid arthritis
Authors: S. Parisi, M.C. Ditto, M. Scarati, M. Priora, F. Enrico
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Methotrexate inhibits the metabolism of purines resulting in the accumulation of adenosine; it also inhibits the activation of T cells and suppresses the expression of intercellular adhesion molecules for T cells. Side effects may show up during the treatment and among them there is hepatic toxicity, characterised by an increase of AST and ALT; such increase is usually asymptomatic but it may lead to a suspension of the treatment. Metadoxine (MTDX) is a drug which is used in order to treat both acute and chronic alcohol intoxication; it also prevents the inactivation of ATP from acetaldehyde and pyroglutamic acid. MTDX also showed to improve hepatic function markers and to decrease oxidative stress leading to a protective effect against radicals. <h3>Objectives</h3> The aim of this preliminary study was to evaluate the possible effect of MTDX on hepatic function in patients affected by RA in therapy with MTX. <h3>Methods</h3> The study involved the recruitment of patients affected by RA in treatment with MTX; a following random selection of a subgroup of patients who took MTDX (500 mg twice a day for 28 days, from the 5th to the 8th week of therapy with MTX) was performed. All the patients underwent a 12-week-follow up in which these parameters were evaluated: demographics, blood tests required for MTX in accordance with datasheets (especially AST and ALT), CRP, ESR, ACPA, numbers of swollen and tender joints, concomitant medications (NSAIDs and steroids) and the degree of disability (HAQ, table 1). <h3>Results</h3> 24 patients affected by RA (20 women), with an mean age of 51.3 years (±14.1) and mean MTX dose of 12.3±2.6, were recruited. 70.3% took GC with a medium dosage (3.72±2.71). Among these 24, 13 patients were underwent MDTX 500 mg twice a day from the 5th to the 8th week. Patients treated with MTDX+MTX showed a significant decrease of hepatic markers (AST Δ−18.38 p=0.004 – ALT Δ−19.23 p=0.004) compare with patients with MTX only (AST Δ−4.27 p=0.110 – ALT Δ−6.09 p=0.045) after a 12-week-monitoring, with no statistically significant difference concerning disease activity (table 2). <h3>Conclusions</h3> This study showed the possible effect of MTDX in increasing the tolerance to the MTX without affecting its effectiveness. Its role may indeed have useful implications in patients who start the therapy with MTX or in those who develop hepatic toxicity during the treatment. <h3>Reference</h3> [1] Fehér J, et al. The Beneficial Effect of Metadoxine in the Treatment of Fatty Liver Diseases. Reviews2009;3(1):65–79. <h3>Disclosure of Interest</h3> None declared
Plasma and cerebrospinal fluid pharmacokinetics of doxil after intravenous administration in adults with primary CNS lymphoma.
Authors: Christine Higham, Robert F. Murphy, Sucharita Bhaumik, Kieron Dunleavy, Wyndham Hopkins Wilson, Brigitte C. Widemann
Journal: Journal of Clinical Oncology (2017)

e14067 Background: Doxil, a pegylated liposomal doxorubicin (PLD) has excellent CNS penetration in rodent brain tumor models and is active in patients with lymphoma. The CNS penetration of doxil in humans is unknown. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of doxil in adults primary CNS lymphoma (PCNSL) as a surrogate for CNS penetration. Methods: Adults with PCNSL enrolled on a NCI phase I study of ibrutinib and multi-agent immune-chemotherapy (NCT02203526) received doxil 50 mg/m2 IV over 1 hour on day 2 of 21-day cycles of chemotherapy. In 4 patients with indwelling Ommaya reservoirs serial blood and CSF samples were obtained prior to infusion and until a median of 345 hours, (range 72-477 hours) after doxil administration. Total doxorubicin concentration (liposome bound + protein bound + free) was quantified with a validated liquid chromatography/tandem mass spectrometry assay (lower limit of quantification plasma=0.29 ng/mL, and CSF=0.06 ng/mL). PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUC CSF :AUC plasma . Results:Total doxorubicin plasma concentration time curves were characterized by sustained drug exposure and a median terminal half-life of 64.5 hours. (range, 61.9-65.1 hours). Doxorubicin was measurable in CSF in all patients, but CSF penetration was low. The terminal half-life of doxorubicin in CSF could not be calculated due to persistently measurable concentrations throughout the sampling times. Conclusions: In patients with PCNSL doxorubicin was measurable in CSF for prolonged time periods after doxil administration, but CSF penetration is low. Clinical trial information: NCT02203526. [Table: see text]