tbuckley/cabot-search huggingface dataset:
Erlotinib plus bevacizumab (EB) versus erlotinib alone (E) as first-line treatment for advanced EGFR mutation–positive non-squamous non–small-cell lung cancer (NSCLC): Survival follow-up results of JO25567.
Authors: Noboru Yamamoto, Takashi Seto, Makoto Nishio, Koichi Goto, Isamu Okamoto, Takeharu Yamanaka, Misa Tanaka, Koji Takahashi, Masahiro Fukuoka, Nobuyuki Yamamoto
Journal: Journal of Clinical Oncology (2018)

9007 Background: In JO25567 (Clinical trials registry number. JapicCTI-111390), EB significantly prolonged progression-free survival (PFS) in patients with NSCLC with activating EGFR mutation compared with E alone. Overall survival (OS) data were immature at the cutoff date for the primary analysis (Seto T et al. Lancet Oncol. 2014;15:1236-44.). We conducted survival follow-up of the patients in JO25567. Methods: JO25567 was open-label randomized trial. Patients with stage 3b/4 or recurrent non-squamous EGFR mutation–positive NSCLC and no previous chemotherapy were randomly allocated to receive EB (E, 150 mg/day; B, 15 mg/kg every 3 weeks) or E (150 mg/day) until disease progression or unacceptable toxicity. Primary endpoint was PFS. To conduct this follow-up, written informed consents were obtained from alive patients. JO25567 data of the patients who were not enrolled into this follow-up due to death or lost to follow-up were also included into this analysis. Results: From 152 patients in JO25567 (EB, n = 75, E, n = 77), 52 patients had died and 25 patients were lost to follow-up at the start of this follow-up. Seventy-five patients (EB, n = 35; E, n = 40) were enrolled between June and October 2014. As of the data cut-off date of 31 October 2017, median OS from random assignment was 47.0 months for EB and 47.4 months for E (HR, 0.81; 95% CI, 0.53-1.23; log-rank p = 0.3267). Forty OS events (53.3%) had occurred in EB and 49 events (63.6%) in E. Five-year survival rate was 41% in EB and 35% in E. There were no major difference of OS between patient characteristics. Sixty-four patients (85.3%) in EB and 65 patients (84.4%) in E received post-study treatments. Conclusions: The median OS around 4 years were observed in both arms. There was a slight trend of survival improvement in EB than E alone, however, the significant difference of PFS was not directly translated into the difference of OS between these treatments. Clinical trial information: JapicCTI-142569.
Estimation of the cumulated exposure to polychlorinated dibenzo-p-dioxins/furans and standardized mortality ratio analysis of cancer mortality by dose in an occupationally exposed cohort.
Authors: D Flesch-Janys, K Steindorf, P Gurn, H Becher
Journal: Environmental Health Perspectives (1998)

For a cohort of 1189 male German former herbicide and insecticide workers with exposure to polychlorinated dibenzo-p-dioxins and -furans (PCDD/F), we report an extended standardized mortality ratio (SMR) analysis based on a new quantitative exposure index. This index characterizes the cumulative lifetime exposure by integrating the estimated concentration of PCDD/F at every point in time (area under the curve). Production department-specific dose rates were derived from blood levels and working histories of 275 workers by applying a first-order kinetic model. These dose rates were used to estimate exposure levels for all cohort members. Total mortality was elevated in the cohort; 413 deaths yielded an SMR of 1.15 (95% confidence interval [Cl] 1.05, 1.27) compared to the mortality of the population of Germany. Overall cancer mortality (n = 124) was significantly increased (SMR = 1.41, 95% Cl 1.17, 1.68). Various cancer sites showed significantly increased SMRs. The exposure index was used for an SMR analysis of total cancer mortality by dose. For 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) a significant trend (p = 0.01) for the SMRs with increasing cumulative PCDD/F exposure was observed. The SMR in the first exposure quartile (0-125.2 ng/kg x years) was 1.24 (95% Cl 0.82, 1.79), increasing to 1.73 (95% Cl 1.21, 2.40) in the last quartile (&gt; or = 2503.0 ng/kg x years). For all congeners combined as toxic equivalencies (TEQ) using international toxic equivalency factors, a significant increase in cancer mortality was observed in the second quartile (360.9-1614.4 ng/kg x years, SMR 1.64; 95% Cl 1.13, 2.29) and the fourth quartile (&gt; or = 5217.7 ng/kg x years TEQ, SMR 1.64, 95% Cl 1.13, 2.29). The trend test was not significant. The results justify the use of this cohort for a quantitative risk assessment for TCDD and to a lesser extent for TEQ.
Comparison of oncometabolite 2-hydroxyglutarate (2HG) levels in mutant isocitrate dehydrogenase (IDH) versus wild-type (WT) glioma tissues.
Authors: Hao-Wen Sim, Gelareh Zadeh, Warren P. Mason, Ken Aldape, Mark Bernstein, Fred Gentili, Mojgan Hodaie, Suneil Kalia, Paul N. Kongkham, Wenjiang Zhang, Takyee Tung, Eric Xueyu Chen
Journal: Journal of Clinical Oncology (2016)

2028 Background: IDH mutations are common and prognostic in low-grade gliomas and secondary glioblastomas. IDH catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (αKG), and subsequently 2HG. Mutant IDH preferentially catalyzes the NADPH-dependent reduction of αKG to R-2-hydroxyglutarate (R-2HG), resulting in accumulation of R-2HG, relative to its enantiomer, S-2-hydroxyglutarate (S-2HG). Previous attempts to correlate plasma/urine 2HG levels with survival and responses to therapies were limited by inconsistent results. Thus, we analyzed R- and S-2HG levels, and ratio of R- to S-2HG (RRS), in glioma tissues from patients with and without IDH mutations. Methods: Fresh frozen glioma tissues were obtained from the University of Toronto Brain Tumor Bank. Diagnosis and IDH status were determined by microscopy and immunohistochemistry. Samples were analyzed using HPLC tandem mass spectrometry coupled with a CHIROBIOTIC R column. Results: Glioma tissues from 4 patients with IDH mutations and 4 WT patients were analyzed. Patient characteristics: M:F ratio: 4:0 for mutant, 3:1 for WT. Age range at surgery: 34-59 for mutant, 47-74 for WT. Tumor size (cm): 2.3-5.4 for mutant, 2.1-8.0 for WT. Location: frontal (2), temporal (1), occipital (1) for mutant, and parietal (1), temporal (2), occipital (1) for WT. Recurrence with treatment effect: 2 of 4 mutant, 3 of 4 WT. Median survival was longer in patients with mutant IDH gliomas (39.9 vs. 17.8 months, p = 0.018). Mutant IDH gliomas had higher total 2HG (mean 451548 vs 2728 ng/g, p = 0.055) and RRS (mean 537.61 vs 0.70, p = 0.022). RRS was 0.36, 0.57, 0.70 and 1.18 in 4 WT patients, and 4.15, 522.75, 543.22 and 1080.34 in 4 mutant patients. Disease-free survival was 6.3, 6.2, 28.3 and 72.0 months respectively for mutant patients with lowest to highest RRS. Conclusions: IDH mutations result in significantly higher RRS in glioma tissues. RRS in glioma tissue, compared with plasma/urine 2HG levels, appears to be a reliable correlate of IDH status. The potential utility of RRS as a prognostic marker warrants further evaluation.
Significant joint-destructive association of HLA-DRB1*04:05 independent of DAS28 in rheumatoid arthritis
Authors: Hideaki Tsuji, Katsunori Ikari, Koichiro Ohmura, Koichiro Yano, Moritoshi Furu, Motomu Hashimoto, Hiromu Ito, Takao Fujii, Wataru Yamamoto, Atsuo Taniguchi, Hisashi Yamanaka, Tsuneyo Mimori, Chikashi Terao
Journal: Annals of the Rheumatic Diseases (2018)

Preventing joint destruction is one of the challenges in rheumatoid arthritis (RA).1 Presence of two antibodies, namely, rheumatoid factor (RF) and cyclic citrullinated peptide antibodies (CCPs), is one of the major correlates of joint destruction.2 We recently showed the association between the progression of joint destruction and HLA-DRB1*04:05, which is independent from CCP positivity.3 HLA-DRB1*04:05 is one of shared epitope (SE) allele carrying common amino acid sequences at position 70–74 frequently found in Japanese and rarely observed in Europeans. Importantly, we showed that SE alleles other than DRB1*04:05 did not show independent associations from CCP.3 

Based on the unique characteristics of HLA-DRB1*04:05, we hypothesised that HLA-DRB1*04:05 might lead to high disease activity not fully captured by Disease Activity Acore 28 (DAS28) and that it independently of DAS28 determines radiographic progression in patients with anti-CCP-positive RA (figure 1A).



Figure 1 
HLA-DRB1*04:05 showed a significant association with SHS independently of DAS28. (A) …
Survival following implementation of next-generation sequencing in routine diagnostics of advanced lung cancer: Results of the German Network Genomic Medicine.
Authors: Anna Kostenko, Sebastian Yves Friedrich Michels, Jana Fassunke, Matthias Scheffler, Sabine Merkelbach-Bruse, Rieke Nila Fischer, Merle Gerigk, Juliane Sueptitz, Florian Kron, Jan Peter Glossmann, Reinhard Buettner, Juergen Wolf
Journal: Journal of Clinical Oncology (2016)

9085 Background: The Network Genomic Medicine (NGM) Lung Cancer is a health care provider network offering comprehensive next generation sequencing (NGS)-based multiplex genotyping on a central diagnostics platform in Cologne for inoperable lung cancer patients (pts) in Germany. Methods: The NGS panel used consists of 14 genes and 102 amplicons to cover potentially targetable aberrations. Mutation analyses were run on an Illumina (MySeq) platform, FISH analyses were performed separately. In 2015, we have started the second outcome evaluation for all NGM pts who had received NGS-based molecular diagnostics. In particular, we have focused on pts with activating EGFR mutation (EGFR+), ALK translocation (ALK+), BRAF-V600E mutation (BRAF+), HER2 amplification (HER2+) and ROS1 translocation (ROS1+) and on the outcome of pts treated in clinical trials (ct). Results: From 2013-2015 6210 lung cancer pts (n = 4244 non-squamous NSCLC) were genotyped. Overall survival (OS) is shown for 934 NSCLC pts including 110 pts treated in ct. For 108 EGFR+ pts, the OS of pts treated in ct with different 3rd generation EGFR-TKIs was 55 months (n = 25) vs 22 months in the control group (n = 83) (p = 0,002; mean OS: 29 months; 95%CI: 36-83 months). For 85 ALK+ pts, the OS of pts treated in ct with next-generation ALK-inhibitor after crizotinib failure was 35 months (n = 19) compared to OS of 23 months for 45 pts treated with crizotinib only and 8 months for 19 pts treated with no ALK inhibitors (p < 0,0001; mean OS: 22 months; 95%CI: 22-33 months). For 32 BRAF+ pts and 11 HER2+ pts, the mean OS was 23 months (95%CI: 12-26 months) and 25 months (95%CI: 15-34 months) (p = 0,022). The mean OS of 13 ROS1+ pts was not reached (95%CI: 58-100 months). Conclusions: Here we show successful implementation of NGS-based molecular diagnostics in clinical routine use. Moreover, molecular diagnostics triggers personalized therapy in – and outside clinical trials and improves survival for EGFR+, ALK+, ROS1+, BRAF+ and HER2+ pts. In particular, the use of next-gen. inhibitors after failure of first gen. inhibitors in EGFR+ and ALK+ pts leads to a significant and substantial additional survival benefit.
Effect of cetuximab on development of viral infectious complications in laryngeal cancer.
Authors: Liubov Yu Vladimirova, Tatiana Zykova, Ludmila A. Ryadinskaya, Marina Engibaryan, Anna E Storozhakova, Natalya A Abramova, Irina L Popova, Natalya Mikhailovna Tikhanovskaya, Aza Agieva, Irina Viktorovna Pustovaya, Yulia Ulianova
Journal: Journal of Clinical Oncology (2017)

e17578 Background: Cytostatic treatment was shown to influence significantly reactivation of latent viral infections. Our purpose was to study the possible effect of cetuximab on activation of herpesvirus infections. Methods: The blood serum of patients with histologically confirmed laryngeal squamous cell carcinoma was studied before and after chemotherapy. The main group included 9 pts receiving cetuximab+cisplatin+5-fluorouracil, the control group – 9 pts, cisplatin+5-fluorouracil. Antibodies (AB) against viral proteins were detected by ELISA. Results: 6 (66.7%) pts of the main group had primary advanced cancer, 3 (33.7%) – recurrent laryngeal cancer; in control group - 7 (77.7%) and 2 (22.2%), respectively. All pts in both groups were seropositive for HSV 1,2, CMV and EBV before chemotherapy; 4 (44.4%) pts in main group and 7 (77.8%) controls were HPV 6 seropositive. Serological markers of activation of herpes virus infection (IgM or IgG against early viral proteins) after chemotherapy were detected in the main group in 8 (88.9%): HSV 1,2 - 5 (55.6%), CMV - 2 (22.2%), EBV - 3 (33.3%). HSV 1,2, CMV and EBV infections in the control group were activated equally often and found in 3 (33.3%) pts. Clinical signs of herpes virus infection were not observed in either group. A sharp decline in AB titers, sometimes up to their complete disappearance, was registered in 3 (33.3%) pts in the main group and in 6 (66.7%) controls. 1 pt of the main group showed a decline in EBV AB titers and absence of HPV 6 AB titers, 1 pt - a decline in CMV and EBV AB, 1 pt - a decline in HSV 1,2, CMV and EBV AB and absence of HPV 6 AB titers. 2 pts of the control group showed a decrease in HPV 6 AB, 2 pts – their absence, 2 pts – absence of HPV 6 AB and a decline in HSV 1,2, CMV and EBV AB. It could be associated with a greater degree of bone marrow hematopoiesis inhibition during cytostatic therapy. Lymphopenia was registered in the control group more frequently than in the main one. Conclusions: Cetuximab inclusion into chemotherapy does not have an additional negative impact on the development of viral infectious complications. A higher rate of registration of specific antibodies typical of the acute infection phase in the cetuximab group could indicate an adequate response to viral infection.
Genome-wide association study of meningioma as a subsequent neoplasm: A report from the Childhood Cancer Survivor Study (CCSS) and St. Jude Lifetime Cohort (SJLIFE).
Authors: Lindsay M. Morton, Joshua N Sampson, Smita Bhatia, Melissa M. Hudson, Ting-Huei Chen, Joseph Philip Neglia, Yutaka Yasui, Eric Karlins, Casey L Dagnall, Todd M. Gibson, Carmen Louise Wilson, Deo Kumar Srivastava, Wei Liu, Guolian Kang, Rita Weathers, Susan A Smith, Margaret A. Tucker, Leslie L. Robison, Stephen J. Chanock, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2016)

10510 Background: Survivors of childhood cancer treated with cranial irradiation have a dose-dependent increased risk of meningiomas, which may cause significant morbidity. However, surveillance guidelines are not well established. Methods: To identify a high-risk population who may benefit from meningioma surveillance, we conducted a genome-wide association study to identify genetic variants predisposing certain childhood cancer survivors to radiation-associated meningioma. The study pooled data from individuals of European descent from CCSS and SJLIFE, including 167 survivors who developed meningioma (median age at meningioma diagnosis = 30.0 years; 84% had 10+ Gy cranial irradiation) and 5732 survivors who did not develop a subsequent neoplasm during follow-up (median age at last follow-up = 33.6 years; 48% had 10+ Gy cranial irradiation). After genotyping and imputation, data were available for 16,958,466 single nucleotide polymorphisms (SNPs) that passed quality control thresholds. We used Cox proportional hazards models with age as the time scale, adjusted for cohort, cranial irradiation 10+ vs.< 10 Gy, receipt of alkylating agent- or platinum-containing chemotherapy, and population eigenvectors to identify associated SNPs. Results: The strongest association was observed for a locus at 7q31.1 marked by rs140784593 (minor allele frequency = 0.01 in controls, 0.04 in cases; per-allele hazard ratio = 7.13, 95% confidence interval = 3.97-12.81; permutation-based P = 1.00x10-8). Results were consistent in both cohorts and also when the pooled population was restricted to children with first primary acute lymphoblastic leukemia or first primary central nervous system tumors. The intergenic SNP rs140784593 maps near GPR85, an evolutionarily-conserved G-protein-coupled receptor involved in intracellular signaling that is highly expressed in the brain. Conclusions: Childhood cancer survivors with inherited predisposition to radiation-associated meningioma may represent a subgroup of individuals who could benefit from more intensive surveillance (e.g., routine magnetic resonance imaging) during long-term follow-up.
Clinical and economic burden of serious adverse events (SAEs) in an early phase trials unit.
Authors: Anna Rachel Minchom, Bindumalini Rao Baikady, Tejaskumar Laxmanbhai Avaiya, Stanley B. Kaye, Udai Banerji, Johann S. De Bono, Juanita Suzanne Lopez
Journal: Journal of Clinical Oncology (2018)

e18890 Background: With increasingly complex early phase trials and the need to closely monitor toxicities, management of SAEs is associated with substantial burden on research units. Detailed costs are often not captured and so not recovered from study sponsors. Methods: Data was prospectively captured on SAEs occurring in patients (pts) participating in early phase trials in the Drug Development Unit (DDU) at Royal Marsden Hospital/Institute of Cancer Research. Event, grade, investigations and management were documented. Time spent on SAEs by health professionals and operational staff was estimated. Costings were calculated using NIHR costing template. Results: Over 12 months, 50 SAEs were reported in 43pts enrolled on 50 trials; 17% of all pts treated (43/247) experienced 1 or more SAE. 88% of SAEs were hospitalizations, 10% medically important. 38% were assessed as study related (Investigational Medicinal Product (IMP) or study procedure related). Median length of hospital stay for study related SAEs was 3 (range 1-16). For study related SAEs all patients underwent clinical assessment and laboratory investigations; radiological imaging was required in 32%; specialist consults in 21%; and specialist tests/procedures in 21%. Median cost of managing each study-related SAE was £1630. Administrative time spent transcribing data on SAE forms was 46 hours over 12 months. Conclusions: Drug-associated costs may differ due to variations in pricing policies and health systems. This is the first comprehensive report of the substantial economic costs of managing SAEs in early phase trials. Accurate costings are necessary to allow costs to be shared with sponsors. Table: Study Related SAEs Non-Study Related SAEs SAE Category Hospitalization 30% (15/50) 58% (29/50) Life Threatening 2% (1/50) Medically Important 8% (4/50) 2% (1/50) SAE Associated Interventions Days hospitalized (median, range) 3 (1-16) 4 (1-26) Radiology (X-ray, CT, USS, MRI) 32% (6/19) 64% (20/31) Specialist consults 21% (4/19) 61% (19/31) Additional investigations/ procedures (e.g. bronchoscopy, ascitic/ pleural drain) 21% (4/19) 23% (7/31) SAE Associated Costs Total cost £63724 £156060 Cost/SAE (median, range) £1630 (£189- £10172) £3922 (£309 - £17689)
Preconditioning of bone marrow-derived mesenchymal stem cells with N-acetyl-L-cysteine enhances bone regeneration via reinforced resistance to oxidative stress
Authors: Jun Watanabe, Masahiro Yamada, Kunimichi Niibe, Maolin Zhang, Takeru Kondo, Minoru Ishibashi, Hiroshi Egusa
Journal: Biomaterials (2018)
Prospective trial of preoperative FOLFIRINOX in patients with resectable pancreatic ductal adenocarcinoma (PDAC): Report of early endpoints.
Authors: Safi Shahda, Michael Garrett House, Nicholas J Zyromski, Amikar Sehdev, Harvey M Cramer, Janet Flynn, Fatih Akisik, Eugene P Ceppa, C. Max Schmidt, Attila Nakeeb, Jingmei Lin, Susan M. Perkins, Heather Burney, Bert H. O'Neil
Journal: Journal of Clinical Oncology (2018)

4118 Background: Chemotherapy and surgical resection improve survival in patients with PDAC. Neoadjuvant therapy (NAT) may allow better selection for resection and provides early treatment of micrometastases. We aimed to assess pathologic response, percent of patients who undergo resection, toxicity, perioperative mortality and survival after NAT in patients with resectable PDAC Methods: Patients with radiographically resectable PDAC were enrolled on this single-arm clinical trial. Patients received FOLFIRINOX (5FU bolus 400 mg/m2, leucovorin 400 mg/m2, 5FU infusion 2400 mg/m2, oxaliplatin 85 mg/m2, and irinotecan 180 mg/m2) on days 1 and 15 of every 28-day cycle. NAT with 2 cycles was followed by restaging imaging prior to surgical exploration and resection. Pathologic response was graded as G1: < 10%, G2: 10-90% and G3 > 90% viable tumor. This study was IRB approved Results: Between 6/2014-10/2017, 51 patients consented and 48 enrolled. Demographics: 30 male and 18 female; median age was 65 years (36-76) and race: 43 W, 3 AA, and 2 other. At the data cutoff (12/31/17), 3 patients have not yet had surgical evaluation. Of 45 patients, 36 have completed all planned preoperative chemotherapy. Thirty-five patients have undergone resection with the following features; R0 margin status: 88%, AJCC7 stage IB: 3%, IIA: 22% and IIB: 74%. Pathologic responses were G1: 6%, G2: 31% and G3: 63% without pathologic CR. Four patients (9%) progressed while on NAT, 3 (7%) were found to have metastatic disease during surgery, and none with local progression prohibiting surgical resection. Two patients died on study; one with complications related to NAT. 30-day postoperative mortality was not observed. Conclusions: NAT is feasible in patients with resectable PDAC and may select out patients with aggressive biology who would not benefit from resection. Pathologic responses were observed without pCR. Survival data are maturing. Clinical trial information: NCT02178709.
A carnosine analog mitigates metabolic disorders of obesity by reducing carbonyl stress
Authors: Ethan J. Anderson, Giulio Vistoli, Lalage A. Katunga, Katsuhiko Funai, Luca Regazzoni, T. Blake Monroe, Ettore Gilardoni, Luca Cannizzaro, Mara Colzani, Danilo De Maddis, Giuseppe Rossoni, Renato Canevotti, Stefania Gagliardi, Marina Carini, Giancarlo Aldini
Journal: Journal of Clinical Investigation (2018)

Sugar- and lipid-derived aldehydes are reactive carbonyl species (RCS) frequently used as surrogate markers of oxidative stress in obesity. A pathogenic role for RCS in metabolic diseases of obesity remains controversial, however, partly because of their highly diffuse and broad reactivity and the lack of specific RCS-scavenging therapies. Naturally occurring histidine dipeptides (e.g., anserine and carnosine) show RCS reactivity, but their therapeutic potential in humans is limited by serum carnosinases. Here, we present the rational design, characterization, and pharmacological evaluation of carnosinol, i.e., (2S)-2-(3-amino propanoylamino)-3-(1H-imidazol-5-yl)propanol, a derivative of carnosine with high oral bioavailability that is resistant to carnosinases. Carnosinol displayed a suitable ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile and was determined to have the greatest potency and selectivity toward α,β-unsaturated aldehydes (e.g., 4-hydroxynonenal, HNE, ACR) among all others reported thus far. In rodent models of diet-induced obesity and metabolic syndrome, carnosinol dose-dependently attenuated HNE adduct formation in liver and skeletal muscle, while simultaneously mitigating inflammation, dyslipidemia, insulin resistance, and steatohepatitis. These improvements in metabolic parameters with carnosinol were not due to changes in energy expenditure, physical activity, adiposity, or body weight. Collectively, our findings illustrate a pathogenic role for RCS in obesity-related metabolic disorders and provide validation for a promising new class of carbonyl-scavenging therapeutic compounds rationally derived from carnosine.