tbuckley/cabot-search huggingface dataset:
Impact of sex on outcomes and adverse events in the advanced biliary tract cancer (ABC)-01 to -04 studies.
Authors: John A. Bridgewater, Andre Lopes, Anna Dorothea Wagner, Juan W. Valle
Journal: Journal of Clinical Oncology (2018)

e16131 Background: The Advanced Biliary Tract Cancer (ABC)-01 and -02 studies established cisplatin and gemcitabine (CisGem) as standard of care for ABC patients. ABC-03 and ABC-04 assessed in addition of targeted agents (cediranib and selumetinib, respectively). Preliminary data from other tumour types suggest greater chemotherapy toxicity in women; it is unclear whether this increased toxicity impacts on outcome. We examine the influence of sex on reported adverse events (AEs) and outcome. Methods: Data were available for BTC patients (pts) in four clinical trials (from 2002 to 2016). All reported AEs were categorized according to the National Cancer Institute’s Common Toxicity Criteria v4.03. Results: Of 547 BTC pts, 281 women and 256 men started treatment. Median duration of treatment was not significantly different according to gender (p = 0.934). Amongst pts who received gemcitabine and cisplatin (the reference regimen), significantly more women had grade 3-4 fatigue and lethargy (8% vs 4%, OR: 1.57, 95%-CI: 1.04; 2.38, p = 0.03), grade 3-4 vomiting (9% vs 5%, OR: 1.97, 95%-CI: 1.00; 3.91, p = 0.05) and any grade nausea (74% vs 56%, OR: 2.25, 95%-CI: 1.57, 3.22, p < 0.001) which may have contributed to more cisplatin dose reductions than in men (22% vs 14%, p = 0.054). All-grade myelosuppression (primarily neutropenia and thrombocytopenia) was significantly increased in men (95% vs 89%, OR: 0.43, 95%-CI: 0.22, 0.85, p = 0.02); leading to more gemcitabine dose reductions compared to women (42% vs 34%, p = 0.06). Overall survival did not differ significantly between women and men (HR: 0.94, 95%-CI: 0.79; 1.12, p = 0.51). Conclusions: Female pts report significantly more fatigue, nausea and vomiting than males and is associated with a greater number of cisplatin dose reductions. Men have significantly more myelosuppression and is associated with more gemcitabine dose reductions. These toxicities and dose modifications did not impact on overall survival.
Mycotoxins: toxicity, carcinogenicity, and the influence of various nutritional conditions
Authors: Paul M. Newberne
Journal: Environmental Health Perspectives (1974)

Toxicologic diseases of man and animals, associated with molds growing on foods, have been recognized for centuries. Only in recent years, however, have these mycotoxicoses received the attention of many laboratories and skilled scientists around the world in a broad inter-disciplinary effort. This review covers the literature on mycotoxicoses but centers on those about which most is known, particularly the diseases associated with metabolites elaborated by some strains of Aspergilli, Penicillia, Fusaria, Stachybotrys, and Claviceps. The ubiquitous nature of the aflatoxins, toxic metabolites produced by Aspergillus flavus, make them important to public health, especially since it is now known that certain areas of endemic liver disease coincide with consumption of aflatoxins and, often, malnutrition. The older disease of ergotism, the scourge of Europe for centuries, is considered in detail. Alimentary toxic aleukia, which has caused enormous suffering in Russian human and animal populations, is better understood as a result of relatively recent experimental investigations. Stachybotryotoxicosis, a disease previously considered to be of significance only to man has now been identified in domestic animals. Finally, Japanese studies have clearly revealed the hepatotoxicity of certain metabolites of Penicillium molds. Factors that influence susceptibility to mycotoxins and the hazards they present to man are also reviewed.
Response rate to lenalidomide plus rituximab (R<sup>2</sup>) as independent of number of prior lines of therapy: Interim analysis of initial phase of MAGNIFY phase IIIb study of R2 followed by maintenance in relapsed/refractory indolent NHL.
Authors: David Andorsky, Morton Coleman, Abdulraheem Yacoub, Jason M. Melear, Heather Dawn Brooks, Suzanne R. Fanning, Kathryn S. Kolibaba, Frederick Lansigan, Chris Reynolds, Jiahui Li, Dongfang Liu, Mary Llorente, Justin L. Ricker, Jeff Porter Sharman
Journal: Journal of Clinical Oncology (2018)

7516 Background: In the relapsed/refractory (R/R) setting for indolent non-Hodgkin lymphoma (iNHL), duration of response (DOR) to and types of prior therapy are important factors in predicting outcomes to subsequent therapy. Lenalidomide plus rituximab (R2) has shown promising efficacy and tolerability in multiple NHL studies. This report explores the association between prior number of therapies and response to R2. Methods: MAGNIFY (NCT01996865) is a phase IIIb, multicenter, global study of R/R NHL patients, including follicular lymphoma (FL) grade 1-3a and marginal zone lymphoma (MZL). Patients receive 12 cycles of R2 (lenalidomide 20 mg/d, d1-21/28 + standard rituximab). Patients with stable disease or better are then randomized 1:1 to maintenance with R2 vs rituximab alone. This analysis focuses on the initial period before randomization (12 cycles R2) for patients with <2 (<2L) vs ≥2 lines (≥2L) of prior systemic anti-lymphoma therapies. Results: As of May 1, 2017, 232 patients with FL gr1-3a (n = 186) and MZL (n = 46) were enrolled for the initial treatment period. Overall, median age was 66 years (range 35-91) and 89% were stage III/IV. Patients received a median of 2 prior systemic treatments (31% ≥3) and 97% received prior rituximab-containing regimens. Analyzed subgroups included 43% <2L (n = 99) and 57% ≥2L (n = 133) with generally similar baseline characteristics. In efficacy-evaluable patients, the overall response rates (70% and 66%) and complete response (51% and 36%) were similar in <2L and ≥2L patients. Median time to response was 2.8 months (range, 2-12) for both groups. For <2L and ≥2L groups, 1-year rates for PFS were 68% and 70%, and DOR were 77% and 81%, respectively. The most common grade ≥3 treatment-emergent adverse events for <2L and ≥2L patients, respectively, were neutropenia (29%; 37%), thrombocytopenia (10%; 6%), and leukopenia (4%; 7%). Conclusions: R2 therapy showed favorable activity and tolerable safety profiles in patients who had R/R FL and MZL, regardless of the number of prior anti-lymphoma therapies. Enrollment in MAGNIFY is ongoing. Clinical trial information: NCT01996865.
Ivosidenib: First Global Approval
Authors: Sohita Dhillon
Journal: Drugs (2018)

Ivosidenib (Tibsovo®) is a small molecule, orally available inhibitor of mutated cytosolic isocitrate dehydrogenase 1 (IDH1) that is being developed by Agios Pharmaceuticals for the treatment of cancer in patients with IDH1 mutations. The mutated form of the IDH1 enzyme produces a metabolite, 2-hydroxyglutarate (2-HG), which is thought to play a role in the formation and progression of acute myeloid leukaemia (AML), gliomas and other cancers. Elevated 2-HG levels interfere with cellular metabolism and epigenetic regulation, thereby contributing to oncogenesis. Ivosidenib targets the IDH1 metabolic pathway to prevent a build-up of the oncometabolite 2-HG. This article summarizes the milestones in the development of ivosidenib leading to this first approval in the USA for the treatment of patients with relapsed or refractory AML with a susceptible IDH1 mutation. Clinical development for AML, cholangiocarcinoma, glioma, myelodysplastic syndromes and solid tumours is ongoing worldwide.
Pharmacist consultation as part of an oral anticancer medication (OAM) outpatient clinic: bridging the gap in care.
Authors: Michelle English
Journal: Journal of Clinical Oncology (2016)

e18211 Background: In recent times the treatment of cancer has changed with the introduction of many oral treatments. There are clear benefits to using the oral route for treatment. Oral therapy however is also associated with risks including toxicity and drug/food interactions and these have been recognised by a number of organisations worldwide. In addition the responsibility for administration of therapy is in the hands of the patient. This requires a high level of patient competence and patient education. There is currently a gap in the care system for patients treated with OAM. We set out to incorporate a pharmacist consultation into an OAM clinic to address this need. Methods: Patients attending the OAM clinic were reviewed by a pharmacist following review by a doctor. Five key performance indicators were identified for target by the pharmacist. These were prescription verification, checking that product dispensed concurred with prescription, counselling on safe handling and correct administration, checking drug interactions with concomitant medication and answering medication related queries. All consultations were documented and interventions recorded. Results: Over a 6 month period, 124 consultations have been recorded for 44 individual patients. A total of 24 interventions were recorded for 20 individual patients (45% of patients). Interventions included: incorrect dose on prescription (n = 1), unclear directions on prescription (n = 1), incorrect strength on label (n = 1), expired product dispensed (n = 1), paracetamol administration with chemotherapy (n = 2), identification of an interacting drug with OAM (n = 18). Outcomes included discontinuing a drug with potential to interact with OAM or switching to a non-interacting drug, enhanced monitoring, dose reduction, change of administration time and liaising with GP or community pharmacist. Conclusions: Our results confirmed there is a need for a pharmacist consultation as part of an OAM clinic, in particular to check drug interactions with concomitant medication. In an era of increased tyrosine kinase prescribing this is of particular importance with potential for increased toxicity or treatment failure due to drug interactions.
Clinical utility of comprehensive approach to detect genetic abnormalities in multiple myeloma.
Authors: Hyun Ae Jung, Mi-Ae Jang, Seok Jin Kim, Kihyun Kim
Journal: Journal of Clinical Oncology (2016)

8034 Background: Recently, identification of genetic abnormalities in multiple myeloma patients is more emphasizing because genetically based risk stratification which significantly affect overall survival. In the recent reports, multiple myeloma with t(4;14) and del(17p) have a poor outcomes, but the associated prognoses are heterogenous and complicated by additional molecular aberrations. The purpose of this study was to investigate the clinical utility of comprehensive approach to detecting genetic abnormalities. In addition, we analyze prognostic significance of the additional genetic abnormalities with t(4;14) and del(17p). Methods: In this study, we investigate the clinical utility of a comprehensive approach (conventional cytogenetic and fluorescence in situ hybridization, FISH) to detect genetic abnormalities of 267 newly diagnosed patients with multiple myeloma. Additionally, we compared the results of conventional FISH and plasma-specific cytoplasmic immunoglobulin FISH, and analyzed the prognostic significance of the genetic abnormalities. Results: By conventional cytogenetic analysis and FISH, 45% (120/267) and 69% (183/267) patients were identified genetic abnormalities, respectively. Among the identified genetic variables, the following factors, which were evaluated by univariate analysis, were found to affect overall survival: abnormal karyotype (P< 0.001), aneuploidy (P= 0.046), -13 or del(13q) (P= 0.002), 1q amplification (P< 0.001), and t(4;14) (P= 0.020). In the multivariate, presence of -13 or del(13q) was only significant genetic factor in overall survival (P= 0.012) with a hazard ratio (HR) of 2.131 (95% confidence interval (CI), 1.185-3.832) as well as the clinical factor of age ( > 65 years) (P= 0.013) with a HR of 2.505 (95% CI, 1.218-5.151). In patients with t(4;14), del13, del 1p or 1q and chromosome 1q gain negatively impacted overall survival. In patients with del(17), del13 and chromosome 1q gain negatively impacted overall survival. Conclusions: Our findings imply the importance of assessment a comprehensive approach to detect genetic abnormalities, as well as it could be closely associated with the prognostic significance of multiple myeloma.
A comprehensive initiative to optimize accrual to neuro oncology clinical trials.
Authors: Mathew England Grubman, Marlon G. Saria, Minhdan Nguyen, Judy Trong, Najee Boucher, Jaya Gill, Anne Heng, Anand A Moses, Tiffany Juarez, Achal Achrol, Steven O'Day, Garni Barkhoudarian, Daniel F. Kelly, Santosh Kesari
Journal: Journal of Clinical Oncology (2018)

e18546 Background: Access to cancer treatment clinical trials is a key measure for the delivery of quality cancer care. When available, cancer clinical trials should be offered up front and practices have been encouraged to strive to achieve an accrual rate of 10% or more. In response to the recommendations, John Wayne Cancer Institute (JWCI) at Providence St. John’s Health Center (PSJHC) began a focused goal over the span of 2 years to increase the number of patients enrolled in neuro oncological clinical trials. While individual barriers to clinical trial participation, including lack of information and personal attitudes and beliefs, have been identified in the literature; suboptimal operational processes such as inconsistent screening and inefficient referrals have often been overlooked. Methods: JWCI at PSJHC created a multiple-approach clinical trial accrual initiative to increase enrollment in clinical trials to optimize efficiency and maximize patient numbers and outcomes. The main process was as follows: (I) PSJHC cancer center leadership and key stakeholders were apprised of the initiative to ensure institutional support for increased access to clinical trials (II) weekly standing meetings were held with the neuro-oncology clinical team to review new patients and availability of slots for clinical trials, (III) discussion was held with providers to trigger referrals of potential research subjects to the clinical team, and (IV) education was conducted among clinicians, non-physician clinicians, nurses, and staff to maximize the accrual of patients to clinical trials in order to have the greatest patient outcomes. Results: Beginning in 2015, seventeen neuro-oncology clinical trials were activated and opened to accrual. From a total of 508 patients seen by the neuro-oncology team, 168 were consented into various clinical trials and 101 were successfully enrolled. Conclusions: Enrollment increased to a total of 19.9% which surpassed the 10% accrual goal. This was achieved by optimizing our operational efficiency through greater screening and increasing referrals.
Cell-free DNA sequencing-guided therapy in a prospective clinical trial: NEXT-2 trial—A feasibility analysis.
Authors: Jeeyun Lee, Seung Tae Kim, Kyoung-Mee Kim, Won Ki Kang, AmirAli Talasaz, Keunchil Park
Journal: Journal of Clinical Oncology (2016)

11534 Background: Analysis of cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is a promising method to identify druggable genomic alterations, especially when tumor specimen is inadequate for genomic sequencing or targeted sequencing. In our previous study, we have demonstrated an extremely high concordance rate between conventional sequencing and ctDNA sequencing. Based on this result, we designed a prospective trial to test the feasibility of the ctDNA genomics and to test the matched therapy rate in metastatic cancer patients focusing on lung cancer, gastric cancer and melanoma. Methods: The trial was a prospective, master protocol, trial with ctDNA genomic profiling and several matched trials were aligned to this protocol as independent trials. Guardant360 is the first comprehensive NGS-based liquid biopsy for cancer which is a 70-gene blood test interrogating all four major types of genomic alterations. Results: From Aug 2014 to Feb 2016, 210 metastatic cancer patients participated in the trial. Of 210 patients, 200 patients had analyzable ctDNA sequencing data (10 patients excluded due to follow-up loss, withdrawal of consent, etc). 73 patients were lung cancer patients, 78 patients were gastric cancer patients, 36 were melanoma patients and the remaining were rare cancer. The major alterations that were found in ctDNA were EGFR amplification, ERBB2 amplification, MET amplification, PIK3CA H1047R/E545K, TP 53 mutations, KRAS Q12, RET fusion, ALK fusion, EGFR mutation, and KIT mutation. Based on the ctDNA sequencing data, patients were directed to the matched therapy in the context of clinical trials or in clinical practice. The median turnaround time from blood draw to the sequencing report was 14 days. Conclusions: In conclusion, we have shown that the feasibility of ctDNA genomics was very high with extremely low failure rate and rapid turnaround time for sequencing report. The matched therapy rate based on ctDNA genomics will be available at the meeting for presentation. Clinical trial information: NCT02140463.
Genetic variations in the β2M/HLA-E immunomodulatory complex to predict outcomes in metastatic colorectal cancer (mCRC) patients (pts) treated with first line FOLFIRI/Cetuximab: Data from the phase III FIRE-3 trial.
Authors: Madiha Naseem, Sebastian Stintzing, Shu Cao, Alberto Puccini, Ryuma Tokunaga, Francesca Battaglin, Afsaneh Barzi, Martin D. Berger, Shivani Soni, Michelle McSkane, Wu Zhang, Joshua Millstein, Volker Heinemann, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

12107 Background: Cetuximab(cet) is an anti-EGFR mAb which enhances the antibody-dependent cellular cytotoxicity (ADCC) by Natural Killer (NK) cells in EGFR+ CRCs. Overexpression of MHC class I antigen E (HLAE), and its membrane stabilizer, βeta-2 microglobulin (β2M) inhibit cet-induced ADCC. We hypothesize that single nucleotide polymorphisms (SNPs) in HLAE/β2M will influence cet-dependent NK cell lysis and clinical outcomes. Methods: Genome wide association studies were conducted on whole blood from 236 mCRC pts in the randomized phase III FIRE-3 trial treated with FOLFIRI/cet(n = 129) and FOLFIRI/bevacizumab(bev)(n = 107). The OncoArray database provided by Illumina containing 530K SNP markers from these pts was used to extract data on 4 functional SNPs from β2M and HLAE. Log-rank test and Cox proportional hazard regression models evaluated SNP associations with PFS/OS in uni- and multivariable analyses. Results: FOLFIRI/cet and FOLFIRI/bev cohort characteristics: median FU (29.1/26.7mo); PFS (12.8/11.5mo); OS (49.8/31.4mo); RAS WT(64%/62%) and RAS mut (15%/16%). Multivariable analysis showed worse PFS in RAS WT pts treated with FOLFIRI/cet with HLAErs1059510 T/T alleles (12.2 vs 13.3 mo; HR = 2.59; 95%CI = 1.05-6.39; p = 0.039) and HLAErs1264457 G/G alleles (12.3 vs 12.9 mo; HR = 2.36; 95%CI = 1.14-4.88; p = 0.021). These effects were not observed in RAS mut pts. β2Mrs1901531 mutant C allele carriers showed improved OS (67.4 vs 40.9 mo) independent of RAS status in FOLFIRI/cet arm in both univariate (HR = 0.27; 95%CI = 0.12-0.59; p < 0.001) and multivariable analysis (HR = 0.19; 95%CI = 0.07-0.48; p < 0.001). No significance was observed in FOLFIRI/bev overall or FOLFIRI/bev RAS WT pts. Conclusions: For the first time, we show that clinical outcomes in mCRC pts treated with FOLFIRI/cet are predicted by genetic variations in HLAE/β2M, which are not observed in FOLFIRI/bev. The predictive utility of HLAE is dependent on RAS status, whereas that of β2M is independent of RAS. The HLAE/β2M complex could be a promising therapeutic target for overcoming cet resistance. Validation in larger cohorts is required.
Survivorship needs after head and neck cancer treatment.
Authors: Callie Berkowitz, Deborah H. Allen, Jennifer Tenhover, Leah L. Zullig, Jonathan E. Fischer, Kathryn I. Pollak, Minoka R. Hicks, John V. Hillson, Bridget F. Koontz
Journal: Journal of Clinical Oncology (2017)

10062 Background: Head and neck cancer (HNC) survivors experience significant sequelae of treatment, including long-term physical side effects and ongoing surveillance for recurrence and secondary malignancy. Given the complicated trajectory of HNC survivors, survivorship care plans educating patients and their caregivers about treatment and recovery may be beneficial. However, little is known about patients’ knowledge gaps related to survivor issues. Methods: Through a prospective anonymous self-administered survey, we evaluated the baseline knowledge of HNC survivors regarding common post-treatment issues and mediating factors. Forty-one HNC patients within 3 months of completing treatment participated between July-November 2016. Descriptive statistics were used to characterize patient responses. Results: Patients had undergone a variety of treatment modalities: radiation (97%), chemotherapy (71%), and surgery (39%). 85% of patients had primary care providers, 56% had regular dental care, and 44% had dental insurance. 78% had caregivers. HNC survivors’ correct responses to side-effect (SE) knowledge questions were lowest for items regarding hearing loss (15%), sleep (33%), tiredness (38%), and anxiety (49%). Only 28% correctly identified cancer risk with alcohol intake. 87% correctly linked tobacco products to cancer recurrence. Patients were most interested in learning via discussions with nurse or doctor (76%) followed by reading written materials (61%), and researching online (32%). Most patients desired to learn more about their cancer (73%), short-term SE (80%), and long-term SE (77%). Conclusions: Our study demonstrated clear gaps in knowledge and healthcare access that may inform targeted, individualized survivorship care plans. Patients had the largest knowledge deficits for alcohol use and recurrence, hearing loss after treatment, and a variety of emotional effects of cancer treatment. These topics should be addressed during delivery of survivorship care plans and surveillance encounters to improve survivorship knowledge.