tbuckley/cabot-search huggingface dataset:
RAS family mutation patterns in a large cohort of CRCs.
Authors: Joanne Xiu, Wafik S. El-Deiry, Paul Campbell, Lanlan Zhou, James S Duncan, Zoran Gatalica, Sandeep K. Reddy, Jonathan Chernoff, Steven J. Cohen
Journal: Journal of Clinical Oncology (2016)

3599 Background: Mutated RAS family members confer resistance to anti-EGFR therapy. We hypothesized RAS family mutations have variable molecular and clinical features including in metastasis of CRC. Methods: We analyzed 3678 CRCs (1992 local tumors and 1685 metastases (mets) including 620 liver, 211 lung, 181 peritoneum, 137 ovary, 19 brain, 15 bone and 4 adrenal) profiled between 2014 and 2016. NextGen sequencing was performed with Illumina MiSeq (TruSeq panel) and NextSeq (Agilent SureSlect XT assay). Microsatellite instability (MSI) was assessed. Results: KRAS mutation occurred in 49% (1791/3640) of CRCs including exon 2 (43.1%), exon 4 (3.3%) and exon 3 (2.7%). Mutation rates were highest in bone (67%), then lung (56%), brain (53%), and no KRAS mutation was found in 4 adrenal mets. Codon 61/146 mutations occurred in brain mets (40%) > local disease (11.6%, p = 0.0234), lung (8.4%), liver (11.5%), ovarian (8%) and peritoneal mets (9.3%). KRAS mutations were more prevalent in MSI-low CRCs (846/1604, 53%) vs MSI-high CRCs (36/101, 36%, p = 0.001). KRAS G12V was the most mutually exclusive of MSI-high (1/199) while 11/138 G13D tumors (8%), 14/274 G12D (5%) tumors and 2/8 K117N CRCs were MSI-positive. NRAS mutation occurred in 3.7% (133/3620) of CRCs, frequently in exon 3 (2.0%), then exon 2 (1.7%), but not in exon 4 or 5. Mutation rate was noted in adrenal (1/4, G12D), brain (1/19, G12D) and ovary (5% or 7/137), but not in bone mets (0/15). NRAS Q61 mutations were more prevalent vs G12/13 in CRCs of local disease (55% vs. 37%), liver (59% vs. 41%) and lung (50% vs. 33%) but were lower than codon 12/13 mutations in ovary (43% vs 57%) and peritoneal (20% vs. 80% ) mets. NRAS Q61K mutations were frequent in local disease (27% of NRAS mutations) and liver mets (30%), but were absent in lung mets (0 of 6 NRAS mutations) and rare in MSI-high CRCs (1/99, A18T). HRAS mutation occurred in 0.3% (11/3223) CRCs, 9 in local disease, including 1 G12D mutation, and 8 variants of unknown significance in exon 2/3. Additional 2 A59T mutations occurred in a liver met and a mesenteric LN. Conclusions: Different codon preferences are mutated within the RAS family in CRC. RAS family mutation codon preferences in metastatic CRC warrant further investigation to elucidate key drivers and personalized therapeutics.
Clinical evaluation of circulating tumor cells in locally advanced nasopharyngeal carcinoma: A prospective study.
Authors: Yuan Wu, Yu Qian, Jun Peng, Xueyan Wei, Zilong Yuan, Fuxiang Zhou, Desheng Hu
Journal: Journal of Clinical Oncology (2017)

e17523 Background: Circulating tumor cells (CTCs) have been showed to correlate with curative effects and prognosis in many cancers, but there are few data describing the importance of CTCs in nasopharyngeal carcinoma (NPC). Our aim was to prospect the karyotyping of CTCs and the correlation between CTCs and clinical response in patients with locally advanced NPC. Methods: Serum was collected in 82 patients with locally advanced NPC. CTC was measured by negative enrichment with immunostaining of CD45, DAPI and imFISH with the centromere of chromosome 8 probe (CEP8) method. Cells with CD45-/DAPI+/CEP8 ≥3 were defined as positive CTCs and the karyotyping of chromosome 8 in CTCs were identified as triploidy, tetraploidy and multiploidy. Patients were treated with 2 cycles of induction chemotherapy followed by concurrent chemoradiotherapy according to the clinical trial (NCT 02562599). CTC was also measured after each cycle of chemotherapy. Clinial response was classified according to the Response Evaluation Criteria in Solid Tumours (RECIST 1.1) criteria. Results: Positive CTCs were detected in 42 of 82 patients prior to treatment. They were independent with age, sex, smoking and clinical stages. Continuous CTC detection of 30 enrolled patients with positive CTCs showed that the ratio of CTCs and CTCs with different ploidies significantly decreased after therapy (P &lt; 0.05). Although the change was not correlated with clinical response (P = 0.054), the decreases in CTCs count of patients who had complete response (CR) to the treatment were significant (P &lt; 0.05), while the decreases of CTCs count of patients who had partial response (PR) were not (P &gt; 0.05). Further analysis indicated that CR patients had fewer tetraploidy CTCs prior to the therapy than PR patients (P &lt; 0.05). Moreover, tetraploidy CTCs count also indicated a positive prediction value for clinical response to treatment according to maximum likelihood estimation (P = 0.045, 95%CI [1.032,18.060]). Conclusions: The decrease of CTCs is correlated with a better therapeutic efficacy in patients with locally advanced NPC and the number of tetraploidy CTCs before treatment could be used as a predictive factor for clinical outcomes.
In vitro characterization and in vivo efficacy of NEOS-518, a novel isoquinoline embedded amino oxazole, that demonstrates CDK-1,2, 3, and 9 inhibition.
Authors: Sara Anne Little, Sumathi Chittamuru, Tim M Murphy, Roseanne Wexler, Laxman Desai
Journal: Journal of Clinical Oncology (2018)

e14509 Background: Cyclin dependent kinases (CDK) play a vital role in cell cycling and proliferation. Altered expression of these kinases in malignant cells results in deregulation of cell cycle activity instigating unregulated growth. NEOS-518 was designed as a CDK inhibitor to modulate expression in malignant cells. Methods: CDK enzyme inhibition assays & kinase binding assays were performed. CYP inhibition assay used human liver microsomes, analyzed by LC-MS/MS. Microsomal clearance determined in mouse, rat, dog, primate, & human, analyzed by LC-MS/MS for percent of parent material. Plasma protein binding was determined by R. E. D. for mouse, rat, dog, primate and human and quantified by LC-MS/MS. AMES reverse mutation assay was conducted. Neo-518 was subjected to the NCI60 human tumor cell screening panel. Ovarian cell line, OVCAR-5 was implanted subcutaneously (SC) in a mouse xenograft model with NEOS-518 delivered QD, IV and measured bi-weekly. Results: Through Lantha screen EU kinase binding assay, > 90% inhibition at 0.1 µM was observed for CDK 5, 6, 8, 11, 13, 14, 16,17, 18. IC50 values for CYP inhibition of > 30 µM for 2C9, 2D6, 2B6 and 2C19. IC50 values of 19.6, 27.2 and 24.2 µM were determined for 3A4, 1A2, and 2C8. Microsomal clearance was high in all species with clearance rates of 61.9 to 111 µL/min/µg. In human liver microsomes a moderate clearance of 29.8 µL/min/µg was observed. High plasma protein binding was observed across species tested from 59.8% to 85.8%. No mutagenicity was observed up to 200 µg. Inhibited cell growth in multiple cell lines including colon, melanoma, ovarian, and breast. NEOS-518 demonstrated 36% growth inhibition over tumor controls after 9 QD doses in a SC OVCAR-5 tumor mouse model. Conclusions: NEOS-518 is a novel CDK inhibitor. The inhibition of several CDK enzymes suggests more complete cell cycle regulation and control over a single kinase target. NEOS-518 demonstrated growth inhibition in both in vitro screening assays and in in vivo mouse tumor model. Assay: % inhibition of NEOS-518 0.1 µM 1.0 µM 10 µM CDC2/CDK1 85.8 97.2 99.5 CDK2 41.5 98.4 98.9 CDK3 67.9 94.3 99.0 CDK9 86.2 99.0 98.3
Using cognitive interviews and expert feedback to validate the Australian AYA Distress Thermometer and Problem Checklist for use in Canada.
Authors: Vicky Rowena Breakey, Norma Mammone D'Agostino, Elena Tsangaris, Anne Klassen
Journal: Journal of Clinical Oncology (2016)

10088 Background: Routine screening for distress is a standard of care for all cancer patients. Since the cancer journey of adolescent and young adults (AYA) is different from that of children and adults, distress screening must be tailored to address their unique issues. The first AYA-specific distress screening tool, The Distress Thermometer and Problem Checklists was developed recently in Australia. Before this tool can be applied in Canada, testing is required to ensure the instructions, response options, and content comprehensively and clearly represent the experience of distress for Canadian AYA. Methods: Interviews were conducted with AYA (15-39 years) in Ontario and Quebec. Feedback from experts in the field of AYA oncology was invited via email. Participants and experts were asked to review the content and provide feedback on the survey items, their relevance and any missing content. Qualitative data analysis involved line-by-line coding of each transcript, applying themes from the preliminary codebook and developing new themes. The codes created were ones that remained close to participants’ descriptions. Codes were organized and refined using the constant comparison method to allow for the development of themes and sub-themes. Interviewing continued until no new codes and categories emerged. Results: Thirty-five AYA were interviewed. All interviews were coded and new items were generated. The most commonly reported areas of distress include physical, emotional, social and “lack of information”. Expert input was sought after the interviews were analyzed and changes were made to the tool. 24/49 (49%) of experts surveyed gave feedback on each item, resulting in the revision of 24/107 items, deletion of 16 items and addition of 28 items. Participants generally endorsed the items with some changes to improve clarity and relevance to Canadian AYA. Conclusions: Stakeholder input has informed revisions of the tool to better reflect the issues faced by Canadian AYA. A second round of cognitive interviews is planned to verify the changes, followed by a Canada-wide field-testing of the reliability and validity of the scale using RASCH analysis.
Dual Inhibition of DNA and Histone Methyltransferases Increases Viral Mimicry in Ovarian Cancer Cells
Authors: Minmin Liu, Stacey L. Thomas, Ashley K. DeWitt, Wanding Zhou, Zachary B. Madaj, Hitoshi Ohtani, Stephen B. Baylin, Gangning Liang, Peter A. Jones
Journal: Cancer Research (2018)

Abstract Ovarian cancer ranks as the most deadly gynecologic cancer, and there is an urgent need to develop more effective therapies. Previous studies have shown that G9A, a histone methyltransferase that catalyzes mono- and dimethylation of histone H3 lysine9, is highly expressed in ovarian cancer tumors, and its overexpression is associated with poor prognosis. Here we report that pharmacologic inhibition of G9A in ovarian cancer cell lines with high levels of G9A expression induces synergistic antitumor effects when combined with the DNA methylation inhibitor (DNMTi) 5-aza-2′-deoxycytidine (5-aza-CdR). These antitumor effects included upregulation of endogenous retroviruses (ERV), activation of the viral defense response, and induction of cell death, which have been termed "viral mimicry" effects induced by DNMTi. G9Ai treatment further reduced H3K9me2 levels within the long terminal repeat regions of ERV, resulting in further increases of ERV expression and enhancing "viral mimicry" effects. In contrast, G9Ai and 5-aza-CdR were not synergistic in cell lines with low basal G9A levels. Taken together, our results suggest that the synergistic effects of combination treatment with DNMTi and G9Ai may serve as a novel therapeutic strategy for patients with ovarian cancer with high levels of G9A expression. Significance: Dual inhibition of DNA methylation and histone H3 lysine 9 dimethylation by 5-aza-CdR and G9Ai results in synergistic upregulation of ERV and induces an antiviral response, serving as a basis for exploring this novel combination treatment in patients with ovarian cancer. Cancer Res; 78(20); 5754–66. ©2018 AACR.
Early impact of a 12-week exercise intervention program on mental health, quality of life and immune markers in early stage breast cancer patients.
Authors: Joan Choo, Yvonne Li'en Ang, Shuk In Tong, Veonice Bijin AU, John Connolly, Huiling Yap, Diana Fransiska, Huey Yen Chia, Germaine Yee, Ednajoy Ngo, Maria Jannet Mogro, Rathi Mahendran, Bee Choo Tai, Gloria HJ Chan, Andrea Li Ann Wong, Natalie Ngoi, Lim Siew Eng, Samuel Guan Wei Ow, Boon C. Goh, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2018)

e12571 Background: Exercise has been shown to have a positive impact on breast cancer survival, but the mechanisms are unclear. Methods: We performed a randomized trial to prospectively study the impact of exercise on physical activity and fitness levels, mental health and quality of life (QOL), plasma immune markers, telomere length/telomerase activity, metabolic hormone levels and survival in early stage breast cancer (BC) patients. Resected stages I-III BC patients are randomized 1:1 to a 12-week, physiotherapist-led, personalized exercise program (Arm A) versus observation (Arm B), 4-12 weeks after completing adjuvant chemo/radiotherapy. Serial assessments were performed at 0, 3, 6, 12 months, and yearly thereafter for 5 years. Results: Fifty-eight of a planned 300 patients have been enrolled (Arm A = 28, Arm B = 30). Median duration of follow up was 16.5 months (range 1-31). Median age was 55 (30-69). 79% had ER+, and 35%/47%/18% had stage I/II/III cancer. 66% each received adjuvant chemo- and radiotherapy. Fitness, mental health and QOL scores were similar in both arms at baseline. Arm A patients had higher QOL scores at 6 months compared to Arm B patients (75 vs 68, p = 0.017). Arm A patients had increased physical activity at 12 months compared to baseline, while this was unchanged in Arm B (median MET-min/week 1620 vs 594 , p = 0.037; 748 vs 693, p = 0.110). Pro-inflammatory cytokines PDGF-AA (mean % change +226% vs +23.5% p = 0.047) and CCL17 (mean % change +47% vs -15%, p = 0.049) were increased at 6 months and 12 months respectively from baseline in Arm A compared to Arm B; while there was a smaller decrease in the anti-inflammatory protein sTNFRII at 6 months from baseline in Arm A compared to Arm B patients (mean % change -4.8% vs -16.2%, p = 0.037). Telomere length and telomerase activity were unchanged at 6 and 12 months in both groups. Conclusions: Early stage BC patients enrolled into a 12-week exercise program had improved QOL at 6 months and increased physical activity at 12 months. Exercise may mediate pro-inflammatory processes with potential impact on survival.
Organoid technology and applications in cancer research
Authors: Hanxiao Xu, Xiaodong Lyu, Ming Yi, Weiheng Zhao, Yongping Song, Kongming Wu
Journal: Journal of Hematology & Oncology (2018)

During the past decade, the three-dimensional organoid technology has sprung up and become more and more popular among researchers. Organoids are the miniatures of in vivo tissues and organs, and faithfully recapitulate the architectures and distinctive functions of a specific organ.These amazing three-dimensional constructs represent a promising, near-physiological model for human cancers, and tremendously support diverse potential applications in cancer research. Up to now, highly efficient establishment of organoids can be achieved from both normal and malignant tissues of patients. Using this bioengineered platform, the links of infection-cancer progression and mutation-carcinogenesis are feasible to be modeled. Another potential application is that organoid technology facilitates drug testing and guides personalized therapy. Although organoids still fail to model immune system accurately, co-cultures of organoids and lymphocytes have been reported in several studies, bringing hope for further application of this technology in immunotherapy. In addition, the potential value in regeneration medicine might be another paramount branch of organoid technology, which might refine current transplantation therapy through the replacement of irreversibly progressively diseased organs with isogenic healthy organoids.In conclusion, organoids represent an excellent preclinical model for human tumors, promoting the translation from basic cancer research to clinical practice. In this review, we outline organoid technology and summarize its applications in cancer research.
Sleep, circadian disruption and neurocognition in breast cancer (BC) patients undergoing chemotherapy.
Authors: Michelle Moore, Melissa Packer, Pasquale F. Innominato, Cheryl Koopman, Shelli Kesler, Oxana Palesh
Journal: Journal of Clinical Oncology (2016)

10072 Background: Up to 70% of cancer patients report cancer-related cognitive impairments (CRCI) during chemotherapy. Good sleep quality and robust circadian rhythmicity are possible modifiable factors for management of CRCI during treatment and the survivorship phase. We tested the relationships between sleep, circadian rest-activity rhythm and CRCI in patients with BC. Methods: 40 Patients (50 years, SD = 11; 53% White, 28% Asian, 19% Other) with primary BC (18% Stage I, 50% Stage II, 33% Stage III) undergoing chemotherapy completed the following neurocognitive battery: Hopkins Verbal Learning Test (assesses verbal memory and learning), Controlled Oral Word Association Test (verbal fluency), and Comprehensive Trail-Making Test (executive function, attention and processing speed). In addition, participants wore a wrist-actigraph (Actiwatch 2; Phillips Respironics) over 7 consecutive days for measuring circadian function (estimated with the dichotomy index I < O), and completed self-report questionnaires of sleep (Pittsburg Sleep Quality Index [PSQI], Insomnia Severity Index [ISI]), fatigue (Brief Fatigue Inventory [BFI]), and depression and anxiety (Clinical Assessment of Depression [CAD]). Results: Better circadian function (higher dichotomy index) was associated with less sleep disruption (PSQI, r = -.44, p = .005) and less insomnia (ISI, r = -.42, p = .008). Both subjective sleep alteration and circadian disruption were associated with significantly higher levels of fatigue (BFI, all p-values < .05) and sleep disruption measures were strongly associated with higher levels of depression and anxiety (ISI: r = .51, p = .001; PSQI: r = .43, p = .005). There were no significant associations found between circadian and sleep disruption variables and neurocognitive measures (p > .05). Consistent with prior studies, no associations were found between CAD and neurocognitive measures (p > .05). Conclusions: These preliminary data suggest that CRCI during chemotherapy might not be associated with either sleep or circadian disruption. It will be important to assess these variables later in the treatment and survivorship course when CRCI tends to become intractable or even progressive in some patients. Clinical trial information: NCT02165839.
Pharmacokinetic study of clofarabine: Oral bioavailability and the effect of cimetidine on renal clearance.
Authors: Matthew Charles Foster, Parag Kumar, Christine Marie Walko, Anastasia Ivanova, Reginald Ewesuedo, Hendrik Van Deventer, Reynaldo Garcia, Steven I. Park, Thomas C. Shea
Journal: Journal of Clinical Oncology (2012)

e13074 Background: Clofarabine (CLO) is a purine analog with activity in myeloid neoplasms. Its oral dosing has been based on an estimated bioavailability (F) of 49% from uncontrolled trials. Animal models suggest that CLO renal clearance (CL) may be impaired in the presence of inhibitors of organic cation transporter-2 (OCT2), which mediates transport across the renal tubular basolateral membrane. We conducted a pharmacokinetic (PK) study of CLO to determine F, and examine the effect of the OCT2 inhibitor, cimetidine (CIM) on intravenous (IV) CLO. Methods: Patients had: 1) untreated AML ≥ 60 years of age unsuited for standard induction, 2) relapsed or refractory AML, or 3) MDS after failure of ≥ 1 prior regimen. Treatment was: CLO 15 mg/m 2 IV day 1, CLO 30 mg/m 2 orally (PO) day 3, CLO 15 mg/m 2 IV day 5 preceded by two doses of oral CIM, and CLO 30 mg/m 2 PO on days 6 and 7. PK studies were obtained after CLO dosing on days 1, 3 and 5. For each dose, CLO plasma concentration was determined, and concentration-time data was analyzed by non-compartmental methods. F was determined for each patient. The geometric means of area under the curve (AUC), 0-∞, and CL for IV CLO administered after CIM doses were compared with AUC and CL for IV CLO administered without CIM. Results: Interim data for the first ten treated patients, with comparisons of PK parameters are shown in the table below. Conclusions: Using patients as their own controls, F of CLO is higher than previously estimated. AUC of CLO is increased and CL is decreased in the presence of CIM, likely owing to inhibition of OCT2-mediated renal tubular secretion. This study is the first human trial to suggest that CLO CL may be impaired in the presence of OCT2 inhibitors, such as cimetidine, trimethoprim, verapamil and nicotine. [Table: see text]
DNA repair defect and RAS mutation in Schistosoma mansoni-associated colorectal cancer patients: Carcinogenesis steps or mere coincidence?
Authors: Gustavo Fernandes Godoy Almeida, Luiz Alberto Reis Mattos, Joao Bosco Oliveira Filho, Paula Carvalho, Bruno Rolim de Brito, Estela Reis Alcantara, Caroline Teixeira Pinto, Filipe W Sarinho, Andre M Galvao, Mauricio Assuero Lima de Freitas, Igor M. L. Snitcovsky, Miriam H.H. Federico
Journal: Journal of Clinical Oncology (2016)

e23279 Background: Data on Schistosoma mansoni-associated colon cancer is scarce. Infestion induces inflammation which may trigger genetic mutations. We report two pts and potentially implicated carcinogenesis. Methods: KRAS/NRAS exons 2, 3 and 4 were amplified by PCR and second-generation sequencing by Illumina MiSeq. Pts were tested for MSI using immunohistochemistry antibodies MLH1, MSH2, MSH6, and PMS2. Results: 1) 45 year-old female, abdominal pain, weight loss and diarrhea. Colonoscopy Oct 2014, 3 cm tumor in cecum. Right colectomy in Jan 2015. Well differentiated mucinous adenocarcinoma. 2.5 x 1.5 x 1.5 cm invasion into muscularis propria. No perineural or lymphovascular invasion. Mild tumor inflammatory infiltrate. Free margins, metastasis to 1 of 24 lymph nodes. Ileal schistosomiasis found. MSI confirmed (loss of MLH1 and PMS2). All-RAS mutation negative. Six-month adj CAPOX. Last visit Dec 2015. 2) 47 year-old male, hepatosplenic form. Right hemicolectomy in 2012 due to complications of appendicitis. Mar 2014, splenectomy and esophageal varices clamp due to GI hemorrhage. He presented diarrhea and in Nov 2014, colonoscopy showed 2 cm tumor next to ileum-transverse colon anastomosis. Mar 2015, segmental colectomy. Ileum: granulomatous reaction in response to Schistosoma eggs; Merkel diverticula; 3.5 x 1.8 cm mucinous moderately differentiated adenocarcinoma infiltrating subserosa, free margins, lymphovascular invasion present, perineural infiltration absent. Mild tumor lymphocytic infiltrate. No lymph nodes were identified in the specimen. Other findings: diffuse granulomatous reaction in response to Schistosoma eggs in ileum and colonic mucosa. MSI negative. Exon 2 KRAS mutation (c.38G > A:p.G13D) was identified. No adj chemo. Last visit Dec 2015. Conclusions: age of patients and mucinous subtype were in accordance with literature. RAS mutation, along with the presence of MSI, may be implicated in the carcinogenesis of Schistosoma mansoni-associated colorectal cancer or represent coincidental events. If the first is right, it would determine screeeing, treatment and prognosis implications among Schistosoma mansoni infested patients.