tbuckley/cabot-search huggingface dataset:
Complementary and alternative medicine and other health behaviors.
Authors: Donna M. Graham, Osvaldo Espin-Garcia, Catherine Brown, Oleksandr Halytskyy, Mary Mahler, Dan Pringle, Lawson Eng, Chongya Niu, Christine Lam, Rebecca Charow, Jodie Villeneuve, Ravi M. Shani, Kyoko Tiessen, Doris Howell, Jennifer M. Jones, Shabbir M.H. Alibhai, Wei Xu, Geoffrey Liu
Journal: Journal of Clinical Oncology (2013)

23 Background: Complementary and alternative medicine (CAM) use in patients with cancer has increased. A patient’s decision to seek CAM alongside conventional cancer treatment is complex. We evaluated whether patients who sought CAM were also more likely to engage in other healthy behaviours such as exercise, smoking cessation, alcohol reduction, and maintaining a healthy weight. Methods: As part of a larger survey of cancer survivors, 551 cancer patients across Princess Margaret Cancer Centre (Canada) were queried on clinico-demographic information, their use of CAM and other health-related behaviors (smoking, alcohol use, healthy weight, etc.). Multivariable logistic regression assessed each health behavior, adjusting for clinical factors associated with CAM use. Results: Females: 53%; median age: 54 years; Caucasian: 83%. Primary tumor sites: breast/gynecologic 22%; gastrointestinal/genitourinary 28%; hematologic 23%; lung/head and neck 12%. Following their cancer diagnosis, 43% used CAM. Being female (odds ratio=2.55, 95% CI [1.8-3.7], having higher education (2.08 [1.4-3.1]) or higher income (1.80 [1.2-2.7]), and having breast/gynaecological cancers (vs. all others; 2.82 [1.8-4.3]) were associated with greater CAM use. These factors served as adjustment variables for the analysis of behaviors. Behaviors associated with increased use of CAM included: use of CAM prior to diagnosis (10.6 [6.5-17.2]), participation in support groups (3.39 [2.1-5.6]), not being overweight or obese one year prior to diagnosis (1.82 [1.2-2.7]), and meeting Canadian physical activity guidelines either before diagnosis (1.80 [1.2-2.8]) or currently (1.70 [1.0-2.8]). No association was observed between CAM use and smoking status or cessation, alcohol intake or reduction, self-described diet habits prior to cancer diagnosis or dietary changes after diagnosis. Conclusions: Some behaviors such as baseline and current physical activity, participation in support groups, not being overweight, and prior use of CAM were each associated with greater CAM use. Smoking, alcohol and diet were not associated with CAM use. Improved understanding of the reasons for CAM use can an improve patient-physician communication, decision-making, and treatment planning.
Variability in safety information in U.S. Package Inserts (USPI) for anticancer agents
Authors: D. A. Rhein, J. F. Worzalla, D. F. Roychowdhury
Journal: Journal of Clinical Oncology (2004)

6068 Background: One purpose of PIs is to provide prescribers' with relevant safety information to make therapeutic decisions. We conducted a review of PIs for anti-cancer agents approved between 1998–2003 to evaluate the presentation of safety information. Methods: Drug listing was obtained from the FDA website (www.fda.gov/cder/cancer/index). Drugs approved for supportive care were excluded as was Busulfex and agents used topically. The safety information in the PI was reviewed and the following information on approval characteristics were noted: tumor type, line of therapy, year of approval, FDA review Center, new drug application (NDA) vs. supplemental NDA (sNDA), regular vs. accelerated approval, approval based on randomized vs. non-randomized (NR) studies, indicated as a single-agent or in combination. Safety information was categorized as adverse event (AE) study-drug related (SDR) vs. all reported AEs, percent cut-off for reporting AEs tables, grade 3/4 AEs (combined vs. separated), comparator AEs reported (Y/N), death, hospitalization or discontinuation due to AEs reported (Y/N), serious AEs (Y/N), AE description in text. Descriptive statistics were used for analysis. Results: There were 40 approvals (21 NDAs, 19 sNDAs) for 27 drugs in 10 tumor types between 1998–2003. Six of 40 approvals were by CBER; 13 of 40 were accelerated approvals. All AEs regardless of drug relatedness were presented in 22 PIs; relatedness was not clarified in 16 PIs. Only SDR AEs were reported in 2 PIs (both approvals based on NR studies). In 7 and 19 PIs, a 10% and 5% cut-off was used in AE tables respectively; and in 14 a cut-off was not stated. Approvals after 2001 had more consistency in reporting AEs based on causality. However, in general, there was considerable variability in the reporting of AEs resulting in death, discontinuation or hospitalization, grade 3/4 AEs and serious AEs. Conclusions: There is considerable variability in the reporting of safety information in USPIs for anti-cancer drugs approved since 1998. Consistent reporting of safety information may help prescribers make appropriate therapeutic decisions, understand risk-benefit and increase the utility of USPIs. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co. Eli Lilly & Co.
A multicenter, randomized phase II study of rilotumumab (R) (AMG 102) or placebo (Pbo) plus mitoxantrone (M) and prednisone (P) in patients (pts) with previously treated castrate-resistant prostate cancer (CRPC).
Authors: Charles J. Ryan, Mark Rosenthal, Siobhan Ng, Joshi J. Alumkal, Joel Picus, Gwenaelle Gravis, Karim Fizazi, Frederic Forget, Jean-Pascal H. Machiels, Min Zhu, Joe Jiang, Sarita Dubey, Elwyn Loh, Winald R. Gerritsen
Journal: Journal of Clinical Oncology (2012)

115 Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor (HGF) that prevents HGF binding to the c-Met receptor. We conducted a 3-arm, double-blind, randomized phase 2 study to examine the safety and estimate the efficacy of adding R to MP in CRPC pts. Methods: Eligible pts (≥ 18 years) had progressive CRPC, prior taxane-based chemotherapy, and ECOG PS ≤ 1. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), PSA response, pharmacokinetics (PK), and safety. Pts were randomized 1:1:1 to R (15 mg/kg IV Q3W) + MP (12 mg/m 2 IV Q3W, 5 mg BID orally) [Arm A]; R (7.5 mg/kg IV Q3W) + MP [Arm B]; or Pbo + MP [Arm C] for up to 12 cycles. Results: 142 pts (Arms A/B/C: 45/48/49 pts) were enrolled between March 10, 2009 and December 2, 2009. Median age: 67/67/69 yrs; ECOG PS 1: 69/71/61%; progression during prior taxane therapy: 51/54/47%. Most common reason for discontinuation was disease progression (60/58/69%). Efficacy is shown in the table. R + MP showed no statistically significant difference in OS. Adverse events (AE) with ≥ 5% difference in Arms A + B vs C included peripheral edema, 24/8%; nausea, 44/35%; mucosal inflammation, 8/0%; rash, 8/0%; arthralgia, 16/8%; neutropenia, 16/8%. Grade 5 AE: cardiac arrest, pulmonary embolism, septic shock (1 each in Arm B). R showed linear PK with mean (SD) steady state C min of 251 (100) and 127 (35) μg/mL and C max of 609 (126) and 297 (75) μg/mL in Arms A and B. R did not affect PK of M. Conclusions: R + MP was well tolerated with no unexpected toxicities. R + MP showed no significant improvements in OS, PFS, and PSA response. [Table: see text]
Phase I and pharmacokinetic (PK) study of STEALTH liposomal CKD-602 (S-CKD602) in patients with advanced solid tumors
Authors: W. C. Zamboni, S. Ramalingam, D. M. Friedland, C. P. Belani, R. G. Stoller, N. B. Modi, R. P. Nath, M. E. Tonda, S. Strychor, R. K. Ramanathan
Journal: Journal of Clinical Oncology (2005)

2069 Background: S-CKD602 is a pegylated STEALTH liposomal formulation of CKD-602, a semi-synthetic analogue of camptothecin. Camptothecins are topoisomerase I interactive agents occurring in equilibrium between the active lactone (LAC) and inactive hydroxy acid (HA) forms. STEALTH liposomes prolong the circulation time in plasma, achieve high drug exposure in tumor, and allow for a convenient schedule of administration. The internal acidic pH of S-CKD602 preserves the LAC form. Results from the first human dose-escalation study are presented. Methods: Patients (pts) were treated with S-CKD602 by 1-h IV infusion once every 3 weeks. Modified Fibonacci escalation was used (3–6 pts/cohort), and dose levels were 0.1, 0.15, 0.2, 0.3, 0.4, 0.5, 0.65, and 0.85 mg/m2. For PK analysis, plasma samples were obtained prior to administration, end of infusion, and at 2, 4, 8, 24, 48, 72, and 96 h after administration, and at days 8 and 15 of cycle 1. Plasma samples were processed to measure concentrations of encapsulated plus released (sum total) S-CKD602 total (LAC + HA) by LC-MS/MS. Results: 30 pts (17 male) have been treated to date: median age 64.5 y (range: 33–79 y); ECOG status: 0 and 1 (29 pts), 2 (1 pt). Frequent toxicities observed include: grade (G) 1 and/or 2 constipation, diarrhea, vomiting, nausea, fatigue, anemia, and leukopenia. One dose-limiting toxicity (DLT) of G3 mucositis was observed at 0.3 mg/m2. G3 leukopenia and G2 thrombocytopenia occurred in 1 pt at 0.85 mg/m2. No additional DLTs were observed and dose escalation continues. 1 pt with hepatocellular carcinoma (10 cycles), and 2 pts with sarcoma (6 cycles each) had stable disease. Mean ± SD AUC of sum total CKD-602 after administration of 0.5 mg/m2 and 0.65 mg/m2 were 7,059 ± 6,444 ng/mL · h and 8,738 ± 9,279 ng/mL · h, respectively, and t\(\frac{1}{2}\) were 22.5 ± 9.3 h and 19.9 ± 7.1 h, respectively. Conclusions: S-CKD602 represents a novel STEALTH formulation of a camptothecin analogue. At doses of 0.5 mg/m2, the plasma AUC is 50-fold higher after administration of S-CKD602 compared to non-liposomal CKD-602 (Curr Opin Investig Drugs 2003:4;1455–9). S-CKD602 has produced minimal toxicity and some suggestion of activity. (Supported by ALZA and NIH/NCCR/GCRC #5M01 RR 00056). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ALZA ALZA ALZA
Tetraspanin CD37 protects against the development of B cell lymphoma
Authors: Charlotte M. de Winde, Sharon Veenbergen, Ken H. Young, Zijun Y. Xu-Monette, Xiao-xiao Wang, Yi Xia, Kausar J. Jabbar, Michiel van den Brand, Alie van der Schaaf, Suraya Elfrink, Inge S. van Houdt, Marion J. Gijbels, Fons A.J. van de Loo, Miranda B. Bennink, Konnie M. Hebeda, Patricia J.T.A. Groenen, J. Han van Krieken, Carl G. Figdor, Annemiek B. van Spriel
Journal: Journal of Clinical Investigation (2016)

Worldwide, B cell non-Hodgkin lymphoma is the most common hematological malignancy and represents a substantial clinical problem. The molecular events that lead to B cell lymphoma are only partially defined. Here, we have provided evidence that deficiency of tetraspanin superfamily member CD37, which is important for B cell function, induces the development of B cell lymphoma. Mice lacking CD37 developed germinal center-derived B cell lymphoma in lymph nodes and spleens with a higher incidence than Bcl2 transgenic mice. We discovered that CD37 interacts with suppressor of cytokine signaling 3 (SOCS3); therefore, absence of CD37 drives tumor development through constitutive activation of the IL-6 signaling pathway. Moreover, animals deficient for both Cd37 and Il6 were fully protected against lymphoma development, confirming the involvement of the IL-6 pathway in driving tumorigenesis. Loss of CD37 on neoplastic cells in patients with diffuse large B cell lymphoma (DLBCL) directly correlated with activation of the IL-6 signaling pathway and with worse progression-free and overall survival. Together, this study identifies CD37 as a tumor suppressor that directly protects against B cell lymphomagenesis and provides a strong rationale for blocking the IL-6 pathway in patients with CD37- B cell malignancies as a possible therapeutic intervention.
NCI-60 gene set connectivity map (GS-CMAP): Connecting pathway-based gene expression profiles for therapeutic efficacy determination
Authors: A. Tan, A. Jimeno, B. Rubio-Viqueira, M. Hidalgo
Journal: Journal of Clinical Oncology (2008)

3588 Background: Dissecting the highly complex cellular regulatory networks and associating gene expression in the context of biological pathways with drug efficacy remain important challenges in personalized medicine. We have developed Gene Set Connectivity Map (GS-CMAP) that connects gene expression in the context of biological pathways with drug efficacy to address these challenges. Methods: We used gene set enrichment analysis (GSEA) to build the NCI-60 GS-CMAP database per KEGG pathway definition. For each cell line in the NCI-60 panel, we used GSEA to obtain rank-ordered pathway list specifics to that cell line. GSEA is performed to generate a query “pathway-expression signature”. To determine the similarity between the query and the NCI-60 panel, the query pathway signature is then compared to each reference signatures in the GS-CMAP database using Spearman’s rank correlation. The top cell line from the sorted list is determined as the connection between the query and NCI-60 panel. Using the top cell line, the query can be linked to the drug sensitivity of that cell line. Results: Thirty pancreatic cancer xenografts treated with gemcitabine with varying relative tumor growth inhibition (TGI) were profiled. When we connect the “pathway-expression signatures” of the thirty xenografts to GS-CMAP, the sensitive cell lines correlates to five sensitive xenografts. More strikingly, the most sensitive xenograft is correlated with the top sensitive cell line. Next, we used GS-CMAP to predict which xenograft will susceptible/resistant to rapamycin. Per GS-CMAP prediction, we treated the most sensitive (PANC219) and most resistant (JH024) xenografts with temsirolimus. TGI values after 28-day of temsirolimus treatment for PANC219 and JH024 are -37% and 90%, respectively; which are correctly correlates to the GS-CMAP prediction. Conclusions: We have demonstrated that GS-CMAP is biologically relevant, and if coupled with an in vivo platform, can be used as a powerful translation research tool in identifying pathway-specific drugs, proposing effective drug combinations, providing opportunities for new target discovery and realizing personalized medicine. No significant financial relationships to disclose.
Clinical and pathological characteristics of Chinese patients with BRCA related breast cancer
Authors: A. Kwong, L. Wong, C. Wong, F. Law, E. Tang, W. Chan, E. S. Ma, J. M. Ford, D. W. West
Journal: Journal of Clinical Oncology (2009)

e22226 Background: Breast cancers due to underlying germline BRCA1 and BRCA2 mutations are associated with particular pathological features that may differ from sporadic breast cancers. We report clinical and pathologic characteristics of breast cancer in a clinical cohort of high risk Chinese women with BRCA mutations and those without mutations. Methods: 202 high risk women based on their age and family history were recruited from March 2007 to November 2008. Medical information was prospectively collected from the patients and medical records. BRCA1 and BRCA2 mutations were detected using full gene sequencing and multiplex ligation-dependent probe amplification (MLPA). Results: Of the 202 female probands tested, 25 (12.3 %) were BRCA mutation carriers of which 11 (44%) were BRCA1 and 14 (56%) were BRCA2 mutations. Breast cancer risk factors, other than family history, did not differ between carriers and non-carriers. Mutation carriers were more likely to have a familial history of breast cancer (p=0.07) and personal and family history of ovarian cancer (p=0.005; p=0.007). Other cancers found in carriers families included pancreatic, gastric, colon, lung, liver, and nasopharyngeal. 23% of women diagnosed with DCIS had BRCA mutations compared with 11.4% of those with invasive cancers. BRCA related tumors were more likely to be ER, PR and Her-2 negative (Triple negative, TN) (p= 0.006). Overall 9.6% of non-BRCA cancers were TN whereas 25.9% of BRCA cancers were TN. Prevalence of TN in BRCA1 carriers is 71% compared with 13.4% in BRCA2 carriers. BRCA1 mutation related cancers were significantly more likely to be ER negative than BRCA2 and this is only significant in those who are under 40 years of age (p=0.070). Conclusions: We have a high BRCA2 mutation rate in our cohort. BRCA related breast cancer is associated with families with increasing number of first degree relatives with breast and/or ovarian cancers and were higher for DCIS cancers. Prevalence of TN breast cancers was high compared to Caucasian cohorts. BRCA mutations were associated with pathologically, poor prognostic features (TN and high grade) especially in younger women. No significant financial relationships to disclose.
Weekly docetaxel (D) and irinotecan (I) in patients (pts) with recurrent or metastatic head and neck cancer (HNC): A phase II trial of the Eastern Cooperative Oncology Group (ECOG)
Authors: A. Argiris, M. A. Goldwasser, B. Brockstein, R. Axelrod, A. Forastiere
Journal: Journal of Clinical Oncology (2005)

5528 Background: D and I have single-agent activity in recurrent or metastatic HNC. This combination is of interest because of partially non-overlapping toxicities and preclinical evidence of synergy. A previous phase I study demonstrated that both drugs can be safely given on a weekly schedule (Cancer Biology and Therapy 2002;1:646). Methods: Pts with recurrent or metastatic squamous cell HNC received D 35 mg/m2 and I 60 mg/m2, intravenously, on days 1 and 8, every 21 days, until disease progression or intolerable toxicities. Eligibility criteria included unidimensionally measurable disease, ECOG performance status 0–1, absolute neutrophil count > 1500/μL, platelets >100,000 μL, and normal bilirubin. Response assessment was performed after every 3 cycles using RECIST criteria. Results: 54 pts have been enrolled: 17 chemotherapy naive (cohort A) and 37 previously treated with 1 prior chemotherapy regimen (cohort B). 78% were males; median age 61 years (32–82); 78% of previously treated patients were paclitaxel-exposed. Response data are available in 47 pts: in cohort A, 4 objective responses (all partial), 3 confirmed and 1 unconfirmed by repeat imaging, were observed in 17 pts (24%); in B, 1 in 30 pts (3%) responded. Median progression-free survival and overall survival were 3.2 and 9.8 months in cohort A and 1.8 and 5.2 months in cohort B. Major toxicities in 51 evaluable pts were: grade (G) 3 /4 neutropenia 8%/10%, G 3 fatigue 16%, G 3 /4 anorexia 8%/4%, G 3 /4 diarrhea 24%/2%, G 3 stomatitis 2%, G 3 /4 vomiting 4%/2%, febrile neutropenia 4%, G 3/4 infection with G 3/4 neutropenia 2%/4%, G 3 /4 dyspnea 2%/2%, and G 3 /4 creatinine 2%/4%. Conclusions: Preliminary analysis shows that D plus I is active in HNC. Toxicities were acceptable and predominantly gastrointestinal. No significant financial relationships to disclose.
Phase II study of the combination of thalidomide and irinotecan in patients with recurrent anaplastic gliomas not on enzyme inducing anticonvulsants
Authors: V. K. Puduvalli, P. Giglio, M. D. Groves, K. R. Hess, M. Gilbert, S. Mahankali, S. Hsu, H. Colman, C. Conrad, V. A. Levin, W. K. Alfred Yung
Journal: Journal of Clinical Oncology (2006)

1564 Background: Patients with recurrent anaplastic glioma (AG) have few treatment options after initial alkylating agent therapy. In this study, the efficacy of thalidomide and irinotecan against recurrent AG was tested to assess if synergistic activity of cytotoxic and antiangiogenic agents could affect clinical outcome. Methods: Patients with recurrent AG with a KPS≥70 not on enzyme inducing anticonvulsants and with fewer than three relapses after radiation therapy and chemotherapies were eligible; the total planned enrollment is 39 patients. Irinotecan is administered at 125 mg/m 2 weekly for 4 weeks followed by 2 weeks rest; thalidomide is initiated at 100 mg daily and escalated weekly up to 400 mg daily. Warfarin (1 mg) is given for prevention of venous thromboembolism (VTE). Patients undergo clinical and radiologic evaluations every 6-weeks. The primary endpoint is progression free survival at 6 months (PFS-6). To determine possible radiologic correlates to treatment effects, DCE- MR perfusion-imaging studies are obtained at baseline and subsequent follow up visits. Results: 17 are evaluable for response; the remainder were inevaluable. All evaluable patients had previously failed temozolomide and 9 had also failed nitrosourea therapy. The median age is 44 yrs and median KPS is 90. Four patients are alive and progression free at 6-months whereas 9 have progressed; the median progression free survival is 23 weeks and the PFS-6 is 34%. The best response was a CR in one patient, PR in 2 and stable disease in 9. Two patients have died of unspecified causes probably related to treatment. Median overall survival has not been reached; the 12-month and 18 month survivals by Kaplan Meier analysis are 73% and 26% respectively. Grade 3 and 4 toxicities included fatigue (29%), leukopenia (29%), nausea/vomitting (24%), and diarrhea (18%) requiring dose reductions. Two patients had VTE. Conclusions: The preliminary results of this ongoing study suggest that the combination of irinotecan and thalidomide has activity in patients with recurrent anaplastic gliomas; the ongoing assessment of this combination in patients with AG will more definitively define whether the combination can be an effective second line therapy for this population. [Table: see text]
A retrospective analysis of patient characteristics and the treatment experience of elderly oncology patients in Kingston, Ontario, Canada
Authors: B. C. Lee, A. Tomiak, W. Hopman
Journal: Journal of Clinical Oncology (2008)

20628 Background: A 2005 study of treatment practices of elderly patients diagnosed before 2000 in Ontario, concluded that age remains a cause of disparity in cancer delivery and that this has remained unchanged over a 30 year period (Journal of Clinical Oncology 23:3802–10). Methods: We performed a retrospective chart review of all elderly patients (age ≥ 75 yrs) referred to the Cancer Centre of Southeastern Ontario in 2006. Patients were identified by a computer search. We collected data on patient demographics (age, gender, marital status, Charlson comorbidity score, cancer type, stage) and treatment (type, intent, acceptance/refusal). Results: A total of 454 patients, representing 17% of all new referrals, were identified. Patient characteristics were as follows: median age 80.0 yrs (75–99), males 49%, married 44.3%, patients with Charlson comorbidity score ≥5 41%. The commonest cancer sites were: gastrointestinal (22%), breast (17%), genitourinary (16%) and lung (15%). 39% of patients had undergone surgery with curative intent; 35% were referred for consideration of palliative treatments. Treatment was discussed and/or recommended as follows: chemotherapy 44%, hormonal therapy 22%, radiation 62%. Acceptance rates were highest for hormonal therapy (92%), intermediate for radiation (77%) and lowest for chemotherapy (47%). 21% of patients did not receive any cancer treatment. In bivariate analysis, the following factors were associated with a higher probability of accepting therapy: chemotherapy - non-palliative intent (p< 0.001), lower Charlson score (≤5) (p=0.003), type of cancer (p<0.001); hormonal therapy - male gender (p=0.036); radiation - married status (p=0.056), age <80 yrs ((p=0.04). Conclusions: We conclude: 1) elderly patients represent a significant proportion of all new referrals to our centre; 2) a substantial portion are referred for consideration of palliative treatments for advanced disease; 3) although hormonal therapy and radiation are associated with high acceptance rates, acceptance rates for chemotherapy are substantially lower, especially in pts with higher Charlson comorbidity scores and in the palliative setting. No significant financial relationships to disclose.