tbuckley/cabot-search huggingface dataset:
Information when patients participate in a phase I trial: A systematic review.
Authors: Katrine Toubro Gad, Ulrik Niels Lassen, Paul Morten Mau Sorensen, Mette Terp Høybye, Christoffer Johansen
Journal: Journal of Clinical Oncology (2017)

85 Background: While phase I trials are essential for the development of new anticancer drugs, there is a limited chance of benefitting for cancer patients participating in such trials. The information dialogue is therefore of substantial importance for providing a foundation to make a decision, and the support from relatives of potential value for the patient. This systematic review investigated patients’ prerequisites for deciding to participate in a phase I trial by summarizing the existing knowledge regarding patients’ decision-making when entering a phase I trial, and patients’ and their relatives’ perception of the information prior to enrollment. Methods: The review is based on the principles of Preferred Reporting Items for Systematic Reviews. A comprehensive systematic search was performed using the PubMed, Embase and PsycInfo databases and supplemented by a search for unpublished literature. Results: We identified 36 studies for inclusion in this review. When patients are offered participation in a phase I trial, information procedures as well as the patients’ individual approach influence the decision-making and the perception of the information provided. Across the studies exploring patients’ perception of information, there was a limited understanding of trial purpose and unrealistic expectations of benefit. The relatives’ perception of information remains unexplored. Evaluation of the included studies demonstrated a comprehensive risk of bias in the majority of studies. Conclusions: The information dialogue between physician and the patient concerning participation in a phase I trial seems to benefit from exact information taking account of the perspectives for each individual patient as well as the need for further discussion of trial. While relatives intuitively function as resources for patients entering a phase I trial, this topic is still not investigated.
Screening of 129 FDA approved anti-cancer drugs in colorectal cancer cell lines resistant to oxaliplatin or irinotecan (SN38).
Authors: Jan Stenvang, Christine Hjorth Andreassen, Nils Brünner
Journal: Journal of Clinical Oncology (2017)

642 Background: In metastatic colorectal cancer (mCRC) only 3 cytotoxic drugs (oxaliplatin, irinotecan and fluorouracil (5-FU)) are approved and the first and second line response rates are about 50% and 10-15%, respectively. Thus, new treatment options are needed. Novel anti-cancer drug candidates are primarily tested in an environment of drug resistance and the majority of novel drug candidates fail during clinical development. Therefore, “repurposing” of drugs has emerged as a promising strategy to apply established drugs in novel indications. The aim of this project was to screen established anti-cancer drugs to identify candidates for testing in mCRC patients relapsing on standard therapy. Methods: We applied 3 parental (drug sensitive) CRC cell lines (HCT116, HT29 and LoVo) and for each cell line also an oxaliplatin and irinotecan (SN38) resistant cell line. We obtained 129 FDA approved anti-cancer drugs from the Developmental Therapeutics Program (DTP) at the National Cancer Institute (NCI) ( https://dtp.cancer.gov/ ). The parental HT29 cell line and the drug resistant sublines HT29-SN38 and HT29-OXPT were exposed to 3 concentrations of each of the anti-cancer drugs. The effect on cell viability was analyzed by MTT assays. Nine of the drugs were analyzed for effect in the LoVo and HCT116 and the SN38- and oxaliplatin-resistant derived cell lines. Results: None of the drugs caused evident differential response between the resistant and sensitive cells or between the SN38 and oxaliplatin resistant cells. The screening confirmed the resistance as the cells displayed resistance to drugs in the same class as the one they were made resistant to. Of the drugs, 45 decreased cell viability in the HT29 parental and oxaliplatin- or SN-38 resistant cell lines. Nine drugs were tested in all nine CRC cell lines and eight decrease cell viability in the nine cell lines. These included drugs in different classes such as epigenetic drugs, antibiotics, mitotic inhibitors and targeted therapies. Conclusions: This study revealed several possible new “repurposing” drugs for CRC therapy, by showing that 45 FDA-approved anti-cancer drugs decrease cell viability in CRC cell lines with acquired drug resistance.
Efficacy and toxicity of sunitinib in renal insufficiency patients with metastatic renal cell carcinoma.
Authors: Ki Hyang Kim, Sun Young Rha, Ho Young Kim, Hye Ryun Kim, Jong-Mu Sun, Ho Yeong Lim, Hyo Jin Lee, Suee Lee, Woo Kyun Bae
Journal: Journal of Clinical Oncology (2013)

e15573 Background: We investigated the efficacy and toxicity of sunitinib in renal insufficiency patients with metastatic renal cell carcinoma (mRCC). Methods: From Korean Renal Cell Cancer Registry (KRCCR, http://kcsg-rcc.or.kr), we searched renal insufficiency patients with mRCC treated with sunitinib as a first-line treatment between January 2008 and May 2012. The Crockcroft-Gault formula was used for calculation of glomerular filtration rate and selected patients with chronic renal failure not requiring dialysis. Patients characteristics, clinical outcomes, toxicities were evaluated. The patients were divided by 2 groups based on the National Kidney Foundation definition of renal impairment and overall survival (OS) and progression-free survival (PFS) were obtained. Results: From total 997 enrolled from KRCCR, 34 patients were evaluated. Patients characteristics included: median age 66 years, ECOG performance status of 0 and 1 were 90%, and median GFR 46.5 ml/min/1.73m2 (range, 21.1-59.5). The starting dose of sunitinib was 50 mg for 22 patients and 37.5 mg for 12 patients. A schedule of sunitinib was 4 weeks on-2 weeks off for 31 patients, 2 weeks on-2 weeks off for 1 patient and daily for 2 patients. Best response was partial response (N=8) or stable disease (N=12). The median OS and PFS was 26.3 (95% CI: 17.1-35.3) and 12.2 (95% CI: 10.2-13.2) months, respectively. Log rank analysis revealed that severity of renal impairment was significantly associated with PFS but not with OS. Most common adverse events (AEs) of non-hematologic toxicities were stomatitis, rash, general edema and fatigue. The most common grade ≥3 AEs were fatigue, neutropenia and thrombocytopenia. Conclusions: Renal insufficiency patients with metastatic RCC did not impact on the efficacy of sunitinib and did not increased toxicities. Clinicians should not hesitate to treat renal insufficiency patients with metastatic renal cell carcinoma.
Protein pathway activation mapping guided biomarker development to identify optimal combinations of MEK inhibitor with PI3K/mTOR pathway inhibitors for the treatment of triple-negative breast cancer.
Authors: Sarah J. Schweber, Alicia G. Rodriguez-LaRocca, Valerie Calvert, Emanuel Petricoin, Susan Band Horwitz, Eleni Andreopoulou, Hayley M. McDaid
Journal: Journal of Clinical Oncology (2013)

2612 Background: Activated MAPK and PI3K pathway signaling are associated with poor prognosis in triple negative breast cancer (TNBC). Although some TNBC cell models are sensitive to MEK inhibition, feedback activation of the PI3K pathway mediates resistance. Thus, suppression of both arms of the MAPK/PI3K/mTOR network is a rational approach to targeting TNBC. Here we explore the anti-tumor efficacy of combinations of MEK inhibitor with PI3K, AKT, or mTOR inhibitors with a focus on biomarker development. Methods: Combinations of the MEK inhibitor PD-0325901 with the PI3K inhibitor GDC-0941, AKT inhibitor MK-2206, dual mTORC 1/2 inhibitor Torin 1, or the rapalog temsirolimus were evaluated in TNBC cell lines. Synergy was assessed using the combination index method of Chou and Talalay. We utilized reverse-phase protein array to map the signaling architecture of the treated lines to verify target suppression and identify pharmacodynamic biomarkers. Results: All combinations demonstrated synergy that was mediated by both suppression of proliferation and cell death in a dose-dependent manner. Cell death was delayed, peaking at least 96 hours post-dosing, and was associated with sustained suppression of target proteins in both pathways, including pERK T202/Y204 , pS6rp S235/236 , p4EBP-1 S65 , and pPRAS40 T246 . However, suppression of pAKT (at T308 or S473) was variable and not consistently required for cell death. Pathway mapping identified a protein network ‘signature’ specific to all combination therapies that emerged at 72 hours and was associated with cell death. Thus, all combinations appear to share common downstream effectors. All combinations showed promising efficacy and will be evaluated in a human-in-mouse model of TNBC. Conclusions: These data support therapeutic strategies for TNBC that simultaneously inhibit both arms of the MAPK/PI3K/mTOR signaling network. For continued biomarker development, we stress the importance of studying the delayed effects of combination therapy. This strategy coupled with a protein network based approach uncovered a unique functional signaling ‘signature’.
Why is it so difficult to enroll patients in clinical trials?
Authors: Norma Kanarek, Dina Lansey, Harold C. Agbahiwe, Julie R. Brahmer, Elizabeth M. Jaffee, Antonio C. Wolff, Vered Stearns, Michael Anthony Carducci, Richard C. Zellars
Journal: Journal of Clinical Oncology (2014)

6552 Background: Nationwide, approximately 3% of patients participate in therapeutic clinical trials. It is presumed that patient education and navigation will increase enrollment. For these interventions to work, a clear understanding of the reasons patients do not enroll is needed. Employing our enrollment framework (Kanarek et al, 2012), we set out to define, at one comprehensive cancer center, the reasons new cancer patients fail to enroll onto clinical trials. Methods: Medical Oncology records from a consecutive series of new breast, non-small cell lung (NSCLC), pancreas and prostate cancer patients were abstracted. Abstraction was based on seven framework sequential steps: 1) trial availability, 2) trial eligibility, 3) physician triage 4) physician-patient discussion, 5) patient’s interest, 6) consent, and 7) enrollment. Each step depends on the prior step (e.g. if there were no trial available then eligibility for a trial could not be considered). Reasons noted for failing any step were summarized. Results: Between 2012 and 2013, records from 688 patients were reviewed. Clinical trial enrollment varied: 5% NSCLC, 12% pancreas and prostate, and 17% breast. The 4 most common reasons for non-enrollment were: no trial available or patient did not meet eligibility (36-55%); standard treatment was recommended or preferred (6-23%); distance from the cancer center (1-22%); and lost to clinical follow-up or patient chose to receive care elsewhere (5-14%). Combined, these 4 reasons eliminate 64% of breast, 83% of pancreas, 84% of prostate and 89% of NSCLC patients from trial participation. About half of the remaining patients enrolled onto clinical trials. Conclusions: Our study suggests that these 4 common reasons for clinical trial non-participation may need to be addressed to increase clinical trial percentages. Patient distribution n(%). n No available trial w/eligibility Distance Sth tx recomm./ preferred Lost to follow up/ care elsewhere Total not available (4 reasons) Remaining available Enrolled on to clinical trials Breast 293 106 (36) 13 (4) 39 (13) 29 (10) 187 (64) 106 (36) 50 (17) Lung 154 78 (51) 2 (1) 36 (23) 21 (14) 137 (89) 17 (11) 8 (5) Pancreas 147 81 (55) 24 (16) 9 (6) 8 (5) 122 (83) 25 (17) 17 (12) Prostate 94 43 (46) 21 (22) 9 (10) 6 (6) 79 (84) 15 (16) 11 (12)
Integrated DNA and RNA next-generation sequencing to enable clinically actionable insights: A precision genomics clinic experience.
Authors: Milan Radovich, Patrick Kiel, Stacy Marie Nance, Erin Niland, David Loesch, Robert James Penny, Bryan P. Schneider
Journal: Journal of Clinical Oncology (2015)

e22076 Background: Incorporation of next-generation sequencing for metastatic cancer patients who have exhausted standard of care options is becoming increasingly popular. Use of an expanded panel that integrates both DNA & RNA markers may help increase the discovery of actionable genomic aberrations. Methods: From Apr-Dec 2014, the Indiana University Health Precision Genomics Program sequenced 161 patients using the Paradigm PCDx Platform. This platform sequences a panel of genes to identify mutations, copy number variation, RNA overexpression, and fusions that are associated with clinical evidence of response. A multi-disciplinary genomics tumor board reviewed all sequencing results. Those patients eligible for the program included metastatic cancer patients with a solid tumor diagnosis who have exhausted standard of care options, or those patients with rare tumors where a standard of care option does not exist. Results: Out of 161 patients sequenced from our precision genomics clinic, 114 (71%) had a genomic aberration that was deemed actionable by our precision genomics tumor board. 56 of the 114 (49%) harbored a potential DNA-based actionable mutation or copy number variant with the most common including: KRAS/HRAS/NRAS (34/56), FGFRs & ligands (9/56), PIK3CA (4/56), and Cyclins (4/56). RNA overexpression provided further actionable results. Of interest, HER2 RNA expression followed by IHC or FISH confirmation assisted in identifying HER2+ cancers in the absence of a copy number variant. In total, 11 patients (non-breast or gastric) had a confirmed HER2 positive cancer. Other RNA markers, such as AREG , CDH1, ER, EREG, hENT1, IGF1R, MET, and VEGFA assisted in further informing therapies or clinical trials. When analyzing by lineage, bladder (n = 11) and colon (n = 22) cancers had the highest percentage of clinically actionable markers as deemed by the tumor board (91% and 86%, respectively), with pancreatic cancer (n = 20) faring the worst (50%). Conclusions: Next-generation sequencing provides clinically actionable information for patients who have exhausted standard of care options. The integration of DNA & RNA markers increases the probability of successful genomic testing.
Pediatric phase 1 study of pemetrexed: A report from the Children’s Oncology Group
Authors: H. S. Nicholson, S. M. Blaney, A. M. Ingle, M. Krailo, L. C. Stork, M. M. Ames, P. C. Adamson
Journal: Journal of Clinical Oncology (2006)

9019 Background: Pemetrexed is a new multi-targeted antifol that inhibits enzymes involved in the de novo biosynthesis of thymidine and purine nucleotides. Methods: A phase 1 dose escalation and pharmacokinetic study (PK) was performed in children with refractory solid tumors to define the dose limiting toxicities (DLTs) and a recommended phase 2 dose. Pemetrexed was administered as a 10 min iv infusion every 21 days. All patients received folic acid (400 mcg/day po), vitamin B12 (500–1000 mcg every 3 rd course IM) and dexamethasone (0.1 mg/kg/dose bid × 3 days each course) . Cohorts of 3 to 6 children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910 and 2,480 mg/m 2 . DLT was defined as any Gr. 3 or 4 non-hematological toxicity (except nausea/vomiting, alopecia, or AST/ALT elevation that returns to Gr. 1), Gr. 4 neutropenia or Gr. 4 thrombocytopenia ≥ 7 days. Results: 33 subjects (31 fully evaluable for toxicity), median age of 12 yrs (range, 1–21), with diagnoses including osteosarcoma (12), Ewing’s sarcoma (3), hepatoblastoma (2), renal cell carcinoma (2), brainstem glioma (3), glioma (3), and other (n=8) were enrolled. DLT occurred in 1/6 patients at 1,470 mg/m 2 (Gr. 3 AST and ALT), and in 2/4 at 2,480 mg/m 2 (Gr. 3 ANC and Gr. 3 rash in both). Other DLTs at 2,480 mg/m 2 that occurred in 1 patient included Gr. 3 diarrhea and rectal hemorrhage, and Gr. 4 thrombocytopenia, lipase, GGT, hypophosphatemia, hypokalemia and hyponatremia. At 1,910 mg/m 2 , 0/6 patients had DLT. The median number of courses administered was 1 (range 1 to 17). No CRs or PRs have been observed. Results of PK and other correlative studies will be presented. Conclusions: The recommended phase 2 dose of pemetrexed for children and adolescents with recurrent solid tumors is 1,910 mg/m 2 administered q21 days with dexamethasone, folic acid and B12 supplementation. A phase II COG study is planned. No significant financial relationships to disclose.
瞬時血流予備量比(iFR)に基づいた生理的に重要な狭窄症に対する光干渉断層法(OCT)の診断精度
Authors: Kikuchi Jun, Matsuo Hitoshi, Kawase Yoshiaki, Okamoto Shuichi, Nakatani Yoshihiro, Kondoh Hiroki, Saigusa Tatsuya, Miyake Taiji, Ohkubo Munenori, Tsuchiya Kunihiko, Hone Junko, Suzuki Takahiko
Journal: Circulation (2015)
LC : Spontaneous fungal peritonitis: a fatal complication in patients with advanced Liver cirrhosis (초)
Authors: Sang Youn Hwang, Jeong Hoon Lee, Su Jong Yu, Joon Suk Kim, Eun Ju Cho, Min Sun Kwak, Eun Sun Jang, Yoon Jun Kim, Jung Hwan Yoon, Eui Chong Kim, Hyo Suk Lee, Chung Yong Kim
Journal: Clinical and Molecular Hepatology (2011)
Assessment of urologists experience with abiraterone acetate and with a real-world trial: Results obtained from a Canadian Observational Study in Metastatic Cancer of the Prostate (COSMiC).
Authors: Andrew Feifer, Vincent Fradet, Darrel Drachenberg, Geoffrey Gotto, Ricardo A. Rendon, Robert Sabbagh, Bobby Shayegan, Brita Lavender Danielson, Richard Casey, Anousheh Zardan, Fernando Camacho, Huong Hew
Journal: Journal of Clinical Oncology (2017)

238 Background: Abiraterone Acetate (AA) is a selective inhibitor of the androgen biosynthesis and has significantly improved OS for mCRPC patients. Canadian Observational Study in Metastatic Cancer of the Prostate (COSMiC) is a Non-Interventional Observational Study pPhase IV clinical trial; NCT02364531) specifically designed to (1) collect real-world drug-specific outcomes (clinical and patient reported outcomes) and (2) assess urologists experience with incorporation of AA in their practice. Here we report data collected from COSMiC trial on the success of AA integration into the urology practice and physicians experience in participating in the trial. Methods: (1) A comprehensive questionnaire was developed to assess urologists experience with (a) integration and usage of AA in their practice and (b) COSMiC trial. (2) Questionnaire was sent to the active trial sites (47 sites) and collected data from 30 sites is summarized here. Results: 93.3% of participants in COSMiC trial were urologists (63.3% community vs. 30% academic). The ease of use and success in integration of AA in urology practice was rated easy by 50% of the participants, easy once they overcame few barriers by 46.7% and challenging by 3.3%. Drug-related barriers identified included time involvement (50%), resource issues such as nursing support (23.3%), and lack of appropriate infrastructure (33.3%). 90% of the active sites indicated that treating mCRPC patients with AA will be part of their practice post-trial. As part of this report we also assessed and identified physicians barriers in participating in COSMiC trial. 86.7% of the sites reported that trials such as COSMiC will add value to the therapeutic area and 93.3% of the sites reported interest in participating in trials of this nature in future. Conclusions: This report indicates that integration of AA in urology practices is considered easy and manageable for most urologists, in some cases after overcoming few initial barriers. There is high interest in participating in future real-world trials of this nature among urologists and such studies add value to the therapeutic area. Clinical trial information: NCT02364531.
Tumor HPV status and invasive squamous cell carcinoma of the anus: Outcomes from a single institution.
Authors: Bhargavi Yalamarti, Mridula George, Lloyd Hutchinson, Ediz Cosar, Louise Maranda, Bradley Alan Switzer, Giles Francis Whalen, Venu Gopal Bathini
Journal: Journal of Clinical Oncology (2014)

4035 Background: Squamous cell carcinomas (SCC) of the anus are associated with infection with Human Papilloma Virus (HPV) genotypes 16 and 18 in 80% of cases. Chemoradiotherapy (CRT) confers 70% 3-year relapse-free survival. Clinical outcomes of anal SCC in relation to common tumor HPV genotypes 16 and 18, has not been reported in patients from the USA. Methods: 81 patients with anal SCC were treated between January 1998 and December 2013 at our institution. Complete data on clinical outcomes and archived specimens for genotyping were available for 62 patients. Tumor HPV status was determined by HPV DNA testing from paraffin-embedded tumor tissues. Results: All 62 patients received radiation therapy > or = 50Gy and 87% received concurrent chemotherapy with 5-FU plus Mitomycin in 90.4% and 5-FU plus Cisplatin in 9.6%. 52 patients (83%) had HPV positive (+) tumors and 46 patients had genotype 16, 3 patients (3/52) had both genotype 16 and 18, 1 had genotype 18. 10 (17%) patients had HPV negative (-) tumors. The mean age at diagnosis for the HPV+ group was 55.06 years, compared to 64.8 years in the HPV- group (p=0.017). The percentage of males in the HPV+ group is 36.5% (19/52) and 60% (6/10) in the HPV- group (p=0.291). In the HPV+ group, 41 patients (78.8%) were T stage 1 to 2, 36 patients (69.2%) had no lymph node (LN) involvement. In the HPV- group, 5 patients (50%) were with T stage 1 to 2 and 5 patients (50%) had no LN involvement. After a median follow up of 7 years, 16/62(25.8%) patients had recurrence of anal cancer and 12 of them were HPV+ with genotype 16. The HPV+ group had longer time to relapse (HR=0.571, [95% CI=0.144 to 2.265], p=0.425) after adjustment for the size of the tumor and nodal status. 4/62(6.4%) patients died, two in the HPV+ and 2 in the HPV- group. 93.5% (58/62) of patients are alive at 5 yrs. In the HPV+ group, 96.1%(50/52) are alive as compared to 80% (8/10) alive in the HPV- group at the end of 5 yrs. The HPV+ group had longer time to death (HR=0.736, [95% CI=0.141 to3.854], p=0.717) after adjustment for tumor size and nodal status Conclusions: In our cohort, HPV+ anal SCC is more commonly diagnosed at a younger age and in women. There was a trend towards longer time to loco-regional relapse and death in HPV+ group than in the HPV- group.