tbuckley/cabot-search huggingface dataset:
Patient characteristics and adverse events (AEs) of tyrosine kinase inhibitors (TKIs) for the treatment of chronic myeloid leukemia (CML) in real world settings.
Authors: Stuart L. Goldberg, Yun Su, Diana Frame, Michael Ryan, William D Irish, Candace Gunnarsson, G. Mabel Woloj, Roxanne Ferdinand, Mark Shapiro
Journal: Journal of Clinical Oncology (2015)

e18026 Background: The growing number of TKIs available for CML increases complexity in choosing therapy in non-research settings. This study aims to determine patient (pt) characteristics & emergent AEs that might underlie treatment choices. Methods: TKI treatment episodes for adult CML pts from 1/2008 - 7/2014 were identified in the MarketScan Commercial, Medicaid, and Medicare supplemental databases. Pts were required to have ≥ 6 mos of enrollment prior to TKI episodes. Analyses were retrospective. Median duration of treatment was assessed using the Kaplan-Meier method. Results: 4,166 TKI treatment episodes for CML were identified. Imatinib (IM) was most commonly used 1st line, dasatinib (DAS) & nilotinib (NIL) 2nd line, and bosutinib (BOS) and ponatinib (PON) 3rd line. BOS pts had the most previous TKI episodes and were furthest from initial diagnosis. They were the oldest, had the highest Charlson Comorbidity Index (CCI), the most histories of vascular occlusive (VO) conditions, kidney diseases, & pleural effusion at baseline (BL), but the lowest rates of serious emergent AEs and discontinuation. With younger age and lower CCI, PON pts had the highest incidences of treatment emergent VO events and fluid retention, with the shortest treatment duration and highest rates of discontinuation. Conclusions: BOS appeared to confer lower risks of serious AEs compared to other TKIs and suited to elderly pts with high comorbidities. The findings need to be confirmed with larger sample sizes. IM n = 1,898 DAS n = 1,180 NIL n = 953 BOS n = 87 PON n = 48 Age (median) 55 52 53 56 51.5 # Prior TKIs (mean) 0.8 1.2 1.2 2.4 2.0 Time since initial diagnosis (median mos) 9 10 11 25 18 CCI (mean) 5.5 5.0 5.4 6.2 5.4 BL /emergent AE (%) VO conditions 31/5 30/6 31/5 43/5 40/15 CHF 11/3 10/4 14/3 23/1 15/6 Dysrhythmias 19/4 18/6 24/9 39/5 35/8 Fluid retention 16/6 17/6 18/5 36/3 33/10 Renal diseases 13/4 11/4 16/3 20/3 19/6 Diabetes 24/6 24/4 23/5 23/2 25/4 Pleural effusion 7/3 10/8 14/4 33/1 29/2 COPD 22/4 22/6 23/3 26/2 23/0 Abdominal pain 32/7 36/7 37/9 45/2 46/10 Diarrhea 14/6 16/5 17/3 24/13 31/8 Treatment Duration (median mos) 16 17 15 13 5 Discontinuation prior to end of follow-up (%) 27 19 24 15 29
A randomized phase II study (VEG108838) of lapatanib plus pazopanib (L+P) versus lapatanib (L) in patients with ErbB2+ inflammatory breast cancer (IBC).
Authors: Massimo Cristofanilli, Stephen R. D. Johnston, Alexey Manikhas, Henry Leonidas Gomez, Oleg Gladkov, Zhimin Shao, Sufia Safina, Stephen D. Rubin, Sulabha Ranganathan, Suman Lata, Maureen E. Trudeau
Journal: Journal of Clinical Oncology (2012)

531 Background: ErbB2 amplification is frequently reported in IBC and there is evidence of positive association between ErbB2 and VEGF expression. We evaluated the combination of anti ErbB2 and VEGF therapy in ErbB2+ IBC. Methods: We conducted a multicenter, randomized clinical trial for patients (pts) with relapsed ErbB2+ IBC. Cohort 1: Pts stratified (prior trastuzumab; cutaneous disease only vs systemic) and randomized 1:1 to receive L 1500 mg + placebo or L 1500 mg + P 800 mg, QD. Due to high incidence of Grade 3/4 diarrhea in pts treated with L 1500 mg+ P 800 mg in another study, Cohort 1 was closed after 76 pts randomized. Cohort 2 (87 pts ): Pts were stratified (prior trastuzumab) and randomized 5:5:2 to receive L 1500 mg + placebo or L 1000 mg + P 400 mg (double-blind) or P 800 mg (open-label), respectively, QD. Treatment continued until PD, unacceptable toxicity or death. Primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety. Results: Cohort 1: 76 pts were randomized and treated: L, n=38; L+P, n=38. ORR was 29% for the L arm, and 45% for the L+P arm. Median PFS was 16.1 and 14.3 wks, respectively, for the L and L+P arms. The most frequent Grade ≥3 AEs were diarrhea (0% vs 18%) vomiting (0% vs 8%), ALT increased (0% vs 8%), neutropenia (3% vs 13%), and bilirubin increased (0% vs 5%). Dose reductions due to AE were 3% and 21% and dose interruptions due to AE were 11% and 55% in the L and L+P arms, respectively. Cohort 2: 88 pts were randomized (87 treated): L, n=36; P, n=14; L+P, n=38. The ORR was 47%, 31%, and 58% for the L, P, and L+P arms, respectively. Median PFS was 16.0, 11.4, and 16.0 wks for the L, P, and L+P arms, respectively. The most frequent Grade ≥3 AEs were ALT increased (0%, 0%, 21%), AST increased (0%, 0%, 18%), diarrhea (3%, 8%, 8%), and fatigue (3%, 8%, 8%). Dose reductions due to AE occurred in 0%, 0%, and 13% of pts and dose interruptions due to AE occurred in 22%, 23%, and 39% of pts in the L, P, and L+P arms, respectively. Conclusions: This prospective, randomized study confirmed the clinical activity of lapatinib single agent in metastatic ErbB2+ IBC. Furthermore, we demonstrated increased toxicity associated with the combination without a clinically meaningful improvement in efficacy.
Gene methylation in random FNA samples as biomarkers for breast cancer.
Authors: Vered Stearns, Seema Ahsan Khan, Mary Jo Fackler, Robert T. Chatterton, Lisa K. Jacobs, Nagi Khouri, Kara Kenney, Christina Shehata, Stacie Jeter, David Ivancic, Judith Wolfman, Carola M. Zalles, Peng Huang, Saraswati Sukumar
Journal: Journal of Clinical Oncology (2012)

518 Background: Current methods to determine breast cancer risk are insufficiently sensitive to select women most likely to benefit from preventive strategies. We hypothesized that candidate gene promoter hypermethylation may provide an individualized risk profile. We performed a prospective study to determine whether DNA cumulative methylation index (CMI) varies by menstrual phase or menopausal status, and to correlate CMI with established risk factors. Methods: We obtained random fine needle aspiration (rFNA) samples from healthy women age 35-60 and determined their menopausal and menstrual status, lifetime Gail risk, mammographic breast density, and cytologic atypia assessed as the Masood score. We evaluated CMI of 11 candidate genes in rFNA cells using the Quantitative Multiplex Methylation-Specific PCR (QM-MSP) technique. We used Wilcoxon test and ANOVA model to compare CMI across menopausal and menstrual (follicular, mid-cycle, luteal) categories, respectively. We used linear regression model to adjust for age and BMI. Methylation scores were log-transformed in the analysis. Results: We enrolled 390 women at the Avon Breast Centers at Johns Hopkins and Northwestern, the majority through the Love/Avon Army of Women, and 380 completed study procedures. Median age 50 (36-60), mean BMI 28 (18.7-50.8), 52% were postmenopausal. Mean life-time Gail risk 14.6 (5.6-54.1), mean percent mammographic density 19.6 (2.5-72.8), and mean Masood score (N=354) 13.6 (7-18). QM-MSP analysis was completed on 229 samples. We did not observe differences in CMI among menopausal (P=0.4895) or menstrual categories (P=0.2333). There was no association between CMI and life-time Gail risk (P=0.706) or breast density (P=0.4116). We observed a significant correlation between CMI and Masood score (P=0.0167). Conclusions: CMI correlates with degree of cytologic atypia and is potentially a robust indicator of breast cancer risk since it does not vary with menstrual or menopausal status. Next, we will select genes that best reflect changes in the clinical parameters to create a gene methylation signature that will be validated in other studies and correlated with breast cancer risk.
Closure of gastric incision with a barbed suture after needlescope-assisted hybrid NOTES
Authors: Miguel Sánchez-Hurtado, Francisco Sánchez-Margallo, Jesús Usón-Casaús, Alejandro Escribano-Crespo, I. Martín-Portugués, Eva Pérez-Merino
Journal: Endoscopy (2017)

Provision of safe peritoneal access without organ injury and guaranteeing secure transluminal closure are two challenging goals in natural orifice transluminal endoscopic surgery (NOTES) [1]. Minilaparoscopically assisted natural orifice surgery (MANOS) is a hybrid NOTES technique that could enable performance of more complex procedures and that can help to avoid the disadvantages of a purely NOTES approach, while minimizing the invasiveness of the laparoscopic procedure [2].
Elevated exhaled nitric oxide in healthy adolescents relates to incident aeroallergen-induced allergic symptoms within 15 years
Authors: Adam Wikström, Pia Kalm-Stephens, Lennart Nordvall, Christer Janson, Kjell Alving, Andrei Malinovschi
Journal: Allergy (2016)

Elevated exhaled nitric oxide in healthy adolescents relates to incident aeroallergen-induced allergic symptoms within 15 years
Mathematical Modeling Links Pregnancy-Associated Changes and Breast Cancer Risk
Authors: Daniel Temko, Yu-Kang Cheng, Kornelia Polyak, Franziska Michor
Journal: Cancer Research (2017)

Recent debate has concentrated on the contribution of bad luck to cancer development. The tight correlation between the number of tissue-specific stem cell divisions and cancer risk of the same tissue suggests that bad luck has an important role to play in tumor development, but the full extent of this contribution remains an open question. Improved understanding of the interplay between extrinsic and intrinsic factors at the molecular level is one promising route to identifying the limits on extrinsic control of tumor initiation, which is highly relevant to cancer prevention. Here, we use a simple mathematical model to show that recent data on the variation in numbers of breast epithelial cells with progenitor features due to pregnancy are sufficient to explain the known protective effect of full-term pregnancy in early adulthood for estrogen receptor-positive (ER+) breast cancer later in life. Our work provides a mechanism for this previously ill-understood effect and illuminates the complex influence of extrinsic factors at the molecular level in breast cancer. These findings represent an important contribution to the ongoing research into the role of bad luck in human tumorigenesis. Cancer Res; 77(11); 2800-9. ©2017 AACR.
Prospective comparative analysis of oncologic and functional outcomes between focal therapy and robotic radical prostatectomy.
Authors: Silvia Garcia Barreras, Rafael Sanchez-Salas, Arjun Sivaraman, Eric Barret, Fernando P. Secin, Cristina Redondo, Guillermo Velilla, Igor Nunes-Silva, Victor Srougi, Gregory Rembeyo, Mohammed Baghdadi, François Rozet, Marc Galiano, Nathalie Cathala, Annick Mombet, Dominic Prapotnich, Xavier Cathelineau
Journal: Journal of Clinical Oncology (2017)

90 Background: Focal therapy (FT) is an emerging treatment alternative for organ-confined Prostate cancer (PCa). The aim is to perform a non-randomized prospective analysis to compare oncological, functional and morbidity outcomes after FT and robotic radical prostatectomy (RARP). Methods: From July 2009 to September 2015, 1883 patients underwent RARP and 373 FT. Of those, we selected 1410 men (1222 RARP and 236 FT) according to the NCCN PCa risk classification: 402(27.5%),388(26.6%) and 668(45.8%) patients were very low risk, low risk and intermediate risk, respectively. Within FT, 188 men underwent focal high-intensity focused ultrasound (HIFU) and 48 cryotherapy. Oncologic outcomes were analyzed in terms of biochemical recurrence (BCR) free survival (Phoenix definition for FT, and PSA &gt;0.2 ng/dl in RARP), and the need for further treatment. FT failure was defined as any positive control biopsy after treatment. Overall suvival and metastasis free survival were estimated using Cox regression and Kaplan-Meier methods. Complications were graded as Clavien-Dindo classification. Functional outcomes were assessed with validated questionnaries for genitourinary symptoms and sexual function. Results: Median follow-up was 45.4 mo (IQR: 25.3-65.5). BCR-free survival was comparable among RARP and FT ( 10.6% RARP vs 9% FT, p 0.69). Patients with intermediate risk PCa were significantly associated with BCR in both groups (HR 8.47;95% CI 4.57-15.71; p&lt; 0.001). In FT group positive biopsy in the treated lobe was seen in 42(17.7%) men. No differences were found in overall survival, neither mestastases free survival between treatments; (p 0.85 and p 0.142 respectively). FT was associated with higher risk of further treatments (HR 5.21; 95% CI 3.7-7.35; p &lt;0.001). FT had higher rates of complications (15.3% vs 9% for RARP, p 0.004). RARP was associated with less continence recovery vs FT at 3, 6 and 12 mo (p &lt;0.001). Potency is higher between FT men at 3,6 and 12 mo (&lt;p 0.001). Conclusions: For selected patients with organ confined PCa, RARP and FT offered comparable oncological control with FT requiring higher additional treatments. Potency and continency appears to be better preserved in FT patients.
A phase Ib dose-escalation study of TRC105 (anti-endoglin antibody) in combination with pazopanib in patients with advanced soft tissue sarcoma (STS).
Authors: Steven Attia, Richard F. Riedel, Steven Ian Robinson, Robert Martin Conry, Kamalesh Kumar Sankhala, Ben K. Seon, Delia Alvarez, Bonne J. Adams, Charles P. Theuer, Robert G. Maki
Journal: Journal of Clinical Oncology (2015)

10514 Background: The VEGFR inhibitor pazopanib is approved for the treatment of advanced STS. Resistance to pazopanib is a challenge in the treatment of STS, and endoglin (CD105) activation may be an important resistance mechanism. Endoglin is an angiogenic receptor expressed on proliferating tumor vessels, which is upregulated following VEGF inhibition and expressed on certain STS subtypes, including angiosarcoma. A phase Ib study of TRC105, an anti-endoglin antibody, in combination with pazopanib was performed in patients (pts) with advanced STS. Methods: Heavily-pretreated STS pts with leiomyosarcoma (11); angiosarcoma (2); synovial sarcoma (2); epithelioid sarcoma (1); myxofibrosarcoma (1); epithelioid hemangioendothelioma (1); and unclassifiable high grade sarcoma (2), ECOG PS 0-1, were treated with infusional TRC105 weekly in two cohorts (8mg/kg and 10mg/kg). TRC105 was initiated following a 2 to 4 week lead-in period of pazopanib starting at 800 mg PO daily. Results: Twenty pts (median age = 57; M:F 9:11; median prior regimens = 2) were treated. Eighteen of twenty pts tolerated pazopanib alone in cycle 1 and received TRC105 beginning with cycle 2. TRC105 dose escalation proceeded from 8 mg/kg (n = 3) to 10 mg/kg (n = 15) without dose limiting toxicity. Grade 1-2 adverse events (AEs) characteristic of each drug were not increased in frequency or severity during concurrent dosing of the two drugs. The most common TRC105 AEs included grade 1-2 telangiectasia (with associated epistaxis and gingival bleeding), while the most common pazopanib AEs included grade 1-2 fatigue and diarrhea. One patient with cutaneous angiosarcoma is ongoing with a complete response, and 5 of 18 pts (28% of those evaluable for efficacy) exhibited > 10% tumor reduction by RECIST 1.1. Duration of therapy ranged from 2 to 12.3+ months. Efficacy endpoints will be correlated with endoglin expression by immunohistochemistry. Conclusions: TRC105 was well tolerated at its recommended phase 2 dose of 10 mg/kg weekly, in combination with daily oral pazopanib, in pts with advanced STS, and the combination exhibited evidence of activity. A multicenter phase 2 trial of TRC105 + pazopanib is ongoing. Clinical trial information: NCT01975519.
A prospective pharmacogenetic study of thymidylate synthase (TS) polymorphisms in high risk stage II or stage III colon cancer patients treated with 5-fluorouracil (5-FU) and leucovorin (LV)
Authors: K. E. Mulder, C. A. Butts, A. Scarfe, H. Au, S. Koski, A. Fields, J. Hanson, M. Kuzma, K. Graham, M. B. Sawyer
Journal: Journal of Clinical Oncology (2006)

13018 Background: Retrospective studies suggest TS polymorphisms predict toxicity from TS inhibitors as well as therapeutic response. The TS promoter has a variable number of tandem repeats (VNTR) polymorphism containing putative E-box binding sites that bind upstream stimulatory factor (USF) -1 and -2. One E-box binding site exists in TSER*2 and 2 binding sites exist in TSER*3. A single nucleotide polymorphism (SNP) at position 12 (G→C) in TSER*3’s 2nd repeat abolishes binding of USF-1/2. Combined effects of VNTR and SNP means individuals may have 2, 3 or 4 enhancer regions. We hypothesized that decreased enhancer numbers predicts for patients at risk for grade ≥3 mucositis, diarrhea, neutropenia, and overall toxicity and performed a prospective pharmacogenetic study of TS polymorphisms in adjuvant colon cancer patients treated with 5-FU/LV. Methods: High risk Stage II or Stage III colon cancer patients treated with 5FU/LV (425 mg/m 2 / 20 mg/m 2 ) daily for 5 days every 4 weeks had blood drawn for genotyping prior to starting therapy. Patients were assessed for toxicity using NCI CTC 2.0 in cycle 1. Three year disease-free survival will also be assessed. Results: 103 patients were enrolled and genotyped with 95 evaluable for toxicity. Patient characteristics: median age 61yrs (36–79): M 52%/F 48%; Stage III 77%, Stage II 23%. Frequency of genotypes containing 2 enhancers (TSER*2/ TSER*2, TSER*2 / TSER*3C, TSER*3C/ TSER*3C), 3 enhancers (TSER*2/ TSER*3G, TSER*3C/ TSER*3G) and 4 enhancers (TSER*3G/ TSER*3G) was 0.64, 0.31, and 0.05 respectively. No significant difference was seen in overall toxicity, mucositis, diarrhea and neutropenia based on TS polymorphism genotypes. Frequency of recurrence in 2 enhancer patients was 13% versus 26% in 3/4 enhancer patients but this did not reach statistical significance (p = 0.16). Conclusions: This prospective study does not confirm previously published retrospective studies suggesting that TS VNTR and SNP predict toxicity from TS inhibitors in patients treated with 5-fluorouracil for colon cancer. There is a trend for prediction of recurrence which requires further follow-up. No significant financial relationships to disclose.
Ibrutinib Monotherapy in Relapse or Refractory Primary CNS Lymphoma (PCNSL) and Primary Vitreo-Retinal Lymphoma (PVRL). Result of the Interim Analysis of the iLOC Phase II Study from the Lysa and the French LOC Network
Authors: Sylvain Choquet, Caroline Houillier, Fontanet Bijou, Roch Houot, Eileen Boyle, Remy Gressin, Emmanuelle Nicolas-Virelizier, Maryline Barrie, Cecile Molucon-Chabrot, Marie Blonski, Abderrazak El Yamani, Marie-Laure LeLez, Aline Clavert, Solène Coisy, Marjan Ertault de la Bretonnière, Valérie Touitou, Nathalie Cassoux, Sami Boussetta, Florence Broussais, Benedicte Gelas-Dore, Noélie Barzic, Herve Ghesquieres, Khê Hoang-Xuan, Carole Soussain
Journal: Blood (2016)
A multi-center phase II study of high dose IL-2 (HD IL-2) sequenced with vemurafenib in patients with BRAF-V600E mutation positive advanced melanoma.
Authors: Joseph Clark, Marc S. Ernstoff, Mohammed M. Milhem, Christopher D. Lao, David H. Lawson, Lawrence E. Flaherty, Theresa L. Luna, Sandra Aung
Journal: Journal of Clinical Oncology (2015)

9053 Background: Durable unmaintained remissions are consistently observed in a small percentage of patients with metastatic melanoma (mM) treated with HD IL-2. Vemurafenib therapy gives rise to a high response rate in BRAF-V600 (BRAF) mutated melanoma patients, but these are relatively short-lived; thus using both drugs in sequence may complement the individual strengths of each therapy. We report the early efficacy and safety results for the PROCLIVITY01 clinical trial of sequenced vemurafenib and HD IL-2. Methods: The primary objective is to assess the CR rate at 10 wks ±3 (assessment 1) and 26 wks ± 3 (assessment 2) from start of HD IL-2. Trial patients were IL-2 eligible and BRAF mutant positive. Cohort 1 patients were treatment naïve and on trial received vemurafenib 960 mg BID for 6 weeks prior to HD IL-2. Cohort 2 patients received vemurafenib for 7-18 weeks prior to enrollment. Both cohorts received HD IL-2 at 600,000 IU/kg every 8 hours for up to 14 doses on days 1-5 and days 15-19. Vemurafenib was held during HD IL-2 treatment. Results: A total of 53 patients received vemurafenib (cohort 1, N = 38); cohort 2 (N = 15). Of these, 40 had assessment 1 and 15 had assessment 2. The overall response rate is14.8% and disease control rate is 51.9% for cohort 1, assessment 1 (n = 27), and 15.4 and 69.2% for cohort 2 (n = 13), respectively. An independent safety committee did not raise safety concerns with the sequencing of these two drugs and patients experienced toxicities as anticipated for IL-2 or vemurafenib. There were no treatment-related deaths. A shift in the melanoma treatment landscape during this trial adversely affected accrual, and led to early trial closure. Conclusions: Vemurafenib given in sequence with HD IL-2 did not change the known toxicity profile for either drug. Early efficacy results reveal low response rates for vemurafenib. Durability of response and long term survival will be reported as patients continue to be followed in the PROCLAIM IL-2 database. Clinical trial information: NCT01683188.
A phase IB study of lenvatinib (E7080) in combination with temozolomide for treatment of advanced melanoma.
Authors: David S. Hong, Corina Andresen, Jennifer Mink, Min Ren, James P. O'Brien, Ly Minh Nguyen, Gerald Steven Falchook, Razelle Kurzrock, John J. Nemunaitis
Journal: Journal of Clinical Oncology (2012)

8594 Background: Lenvatinib is an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. In phase I studies of lenvatinib partial responses were observed in melanoma as well as thyroid, endometrial, and renal cancers. Methods: Patients (pts) with stage 4 or unresectable stage 3 melanoma were treated in sequential cohorts of escalating doses of lenvatinib by continuous once daily dosing and temozolomide (TMZ) days 1-5 every 28 days. Cohort 1: lenvatinib 20mg, TMZ 100 mg; cohort 2: lenvatinib 24 mg, TMZ 100 mg; cohort 3: lenvatinib 24 mg, TMZ 150 mg. Adverse events were recorded according to CTCAE v3.0 and tumor response assessed according to RECIST 1.0. Results: 32 pts were treated: cohort 1: 6 pts, cohort 2: 4 pts, cohort 3: 22 pts. Demographics: median age: 58; males: 63%. Dose limiting toxicities occurred in 0/6 pts in cohort 3 leading to cohort expansion to a total of 22 pts to enable more extensive assessment of toxicity and a preliminary estimate of efficacy. The most common treatment related adverse events in the cohort 3 were fatigue: 50% (gr3: 9%), hypertension: 50% (gr3: 9%), proteinuria: 50% (no gr3), vomiting: 46% (no gr3), hypothyroidism: 46% (no gr3), anorexia: 41% (no gr3), nausea: 41% (no gr3), diarrhea: 36% (gr3: 5%), thrombocytopenia: 32% (no gr3). No treatment-related gr4 events were reported in these categories. The best overall responses per RECIST were partial responses: 5/22 (23%) for cohort 3 pts and 6/32 (19%) for all pts treated at all dose levels. Six-month progression free survival (PFS) rate was 37% and median PFS was 5.4 months. PK/PD analysis and correlation of response with genetic mutational status (BRAF mutations in 31% pts; NRAS mutations in 19% pts) will be presented. Conclusions: Lenvatinib 24 mg once daily in combination with TMZ 150 mg days1-5 every 28 days was given without apparent worsening of either lenvatinib or TMZ related toxicities. Modest clinical efficacy for this combination was observed.