tbuckley/cabot-search huggingface dataset:
Cytogenetic and molecular testing in patients with chronic myeloid leukemia (CML) in a prospective observational study (SIMPLICITY).
Authors: Stuart L. Goldberg, Jorge E. Cortes, Carlo Gambacorti-Passerini, Rüdiger Hehlmann, Hanna Jean Khoury, Michael J. Mauro, Mauricette Michallet, Ronald Paquette, Bengt Simonsson, Aimee Foreman, Hesham Mohamed, Milayna Subar, Teresa Maria Zyczynski
Journal: Journal of Clinical Oncology (2014)

7050 Background: Few clinical practice data describe response monitoring in patients (pts) with chronic-phase CML (CP-CML) treated with tyrosine kinase inhibitors (TKIs). Methods: SIMPLICITY is an ongoing observational study of CP-CML patients receiving first-line imatinib (IM), dasatinib (DAS) or nilotinib (NIL) in the United States (US) and Europe (EU); its primary objective is to understand TKI use and management patterns in clinical practice (NCT01244750). The study includes 3 ‘prospective’ newly-diagnosed cohorts treated with IM, DAS or NIL since 2010 and a ‘historical’ cohort treated with IM since 2008. Frequency of testing for cytogenetic response (CyR), by FISH or karyotype, and molecular response (MR), by PCR, were analyzed in 6 and 12 month increments from TKI start. Results: 949 pts (EU: 34%, US: 66%) were enrolled through 10/03/2013, receiving IM (n=415), DAS (n=275) or NIL (n=259). Mean (± SD) follow-up was 19 (± 9) months. Demographics were consistent across cohorts (median age: 56 years; 56% male). Of 713 pts with ≥12 months’ follow-up, 48% were tested for CyR between 0–12 months (excluding diagnostic tests); of these, 40%, 33% and 28% had 1, 2 and ≥3 tests, respectively. The proportion of pts tested for CyR in the first 12 months varied by region (EU: 62%; US: 42%). The proportion of pts with ≥12 months follow-up that were tested for MR between 0–12 months was 80% across regions (EU: 85%; US: 78%); of these, 28%, 31%, and 41% had 1, 2 and ≥3 tests, respectively. Of 1,399 reported MR tests, 72% used the International Scale (IS), 6% did not use the IS and 22% were listed as ‘unknown’. The proportion of MR tests that used the IS in EU and US was 86% and 65%, respectively. Of 713 pts, 113 (16%) had neither CyR nor MR testing and 600 (84%) had either a CyR or a MR test in the first 12 months. Comparison of these data with a follow-up independent survey of SIMPLICITY investigators, and monitoring patterns by practice type, will be presented. Conclusions: Response monitoring in clinical practice differs from ELN and NCCN recommendations and shows regional variation. More pts are monitored for MR than CyR, with a more pronounced difference between the US and EU in frequency of CyR testing than in MR testing.
Is seroma formation after breast conserving surgery influenced by intraoperative radiation therapy (IORT)?
Authors: Nikolaus de Gregorio, Thomas W. P. Friedl, Dirk Bottke, Thomas Wiegel, Elena Vorwerk, Amelie Schramm, Fabienne Schochter, Jens Bodo Huober, Christoph Scholz, Achim Wöckel, Andreas Rempen, Wolfgang Janni, Florian Ebner
Journal: Journal of Clinical Oncology (2015)

e12049 Background: One of the most common complications in breast surgery is seroma formation. The origin of seroma formation remains unclear, but omitting a wound drain in breast surgery has been shown to be possible. With new treatment options like IORT extrapolation of the existing data is not feasible. Therefore this analysis compares seroma production in patients with breast conserving surgery +/- IORT as a tumor bed boost during breast conserving surgery. Methods: We performed a retrospective comparison of seroma production in patients with nodal-negative (pN0sn) pT1/2 primary breast cancer treated between September 2010 and October 2013 at the Breast Cancer Center, University Hospital Ulm. Patients with neoadjuvant chemotherapy, previous breast/axillary surgery or more than one intervention were excluded. In selected patients IORT was applied as a tumor bed boost with 50-kV X-rays (Intrabeam) delivering 9 Gy at the applicator surface. Seroma formation was measured using wound drains placed in the breast and in the axilla. Results: Patients were well balanced regarding age, menopausal status, hormone-receptor and HER2 receptor status with slightly more pT2 tumors in the non IORT group. A seperate analysis for pT1/2 subgroups did not change the results (surgery n = 99; IORT n = 53). There were no significant differences between the two groups with regard to the amount of seroma production in the breast (with IORT: median 50 ml, range 15 – 304 ml; without IORT: median 50 ml, range 2 – 343 ml; p = 0.879) or in the axilla (with IORT: median 49 ml, range 10 – 240 ml; without IORT: median 40 ml, range 10 – 285 ml; p = 0.833). In addition, there were no significant differences in number of days until removal of breast drains (with IORT: median 3 days, range 1 – 6 days; without IORT: median 3 days, range 2 – 6 days; p = 0.340) or axilla drains (with IORT: median 3 days, range 1 – 4 days; without IORT: median 3 days, range 2 – 6 days; p = 0.449). Conclusions: Patients with IORT had no increased seroma production and no later removal of the drains compared to patients with breast conserving surgery only. Our results indicate that IORT does not increase the seroma production compared to surgery alone.
FOLFIRI as second-line (2L) treatment of metastatic gastric cancer (mGC) in clinical practice: Efficacy, safety, and prognostic factors.
Authors: Miguel J. Sotelo, Carlos Aguado, Javier Sastre, Beatriz García-Paredes, Aránzazu Manzano, Mónica Granja, Gloria Marquina, Hector R. Callata Carhuapoma, Daniel Alejandro Acosta Eyzaguirre, Jose-Luis Gonzalez-Larriba, Santiago Cabezas, Eduardo Diaz-Rubio
Journal: Journal of Clinical Oncology (2014)

e15053 Background: There is no standard treatment of 2L for mGC. Irinotecan has been shown to increase overall survival (OS) in this setting. FOLFIRI is an active and well-tolerated regimen which has previously been tested in phase II studies in both first-line (1L) and 2L. Methods: Retrospective study of patients (pts) with mGC who were treated in 2L with FOLFIRI (Irinotecan 180mg/m2 d1, Leucovorin 400mg/m2 and 5FU 400mg/m2 d1, followed 5FU 2400mg/m2in a 46h continuous infusion, every 2 weeks). We assessed response rate, clinical benefit rate (CBR), progression-free survival (PFS), OS and toxicity. Univariate analysis was performed to correlate the clinicopathological characteristics with PFS and OS. Results: 66 pts were included. Median age: 65y. 80% of pts had ECOG ≤1. Number of metastatic sites (NMS): 1 (41%), ≥2 (59%). Most common regimens in 1L: TPF (30%), CDDP-Capecitabine (30%) and CDDP-5FU (26%). Median of number cycles: 7. 55 pts were evaluable for response: complete response 4%, partial response 16% and stable disease 34%. CBR: 40% (11 pts had disease stabilization for ≥6m). Median PFS was 3m and median OS 6m. NMS (≥2 vs 1) was found to be a prognostic factor for PFS (3 vs 6m, HR 2.23, p=0.005) and OS (4 vs 15m, HR 2.71, p<0.001). PFS in 1L (PFS1L) (<7m vs ≥7m) was a prognostic factor for OS (4 vs 9m, HR 1.71, p=0.045), but not for PFS (3 vs 4m, HR 1.37, p=0.226). PFS1L <7m and ≥2 metastatic sites were identified as poor prognostic factors. We defined 2 prognostic groups: good prognosis (one metastatic site and PFS1L ≥7m) and poor prognosis (PFS1L <7m and/or ≥2 metastatic sites). Pts in the poor prognostic group had a significantly worse PFS (3 vs 5m, HR 2.08, p=0.030) and OS (4 vs 17m, HR 2.97, p=0.003), compared with pts in the good prognosis group. The most common grade 3-4 toxicity was neutropenia 27%, asthenia 17%, leukopenia 12%, anemia 11% and diarrhea 9%. There were 2 cases of neutropenic fever, leading to death in one of them. Conclusions: FOLFIRI is effective and well-tolerated as 2L treatment of mGC. NMS and PFS1L are prognostic factors in this group of pts. Phase III studies are needed to demonstrate the superiority of FOLFIRI versus irinotecan monotherapy in this setting.
Progression-free survival (PFS) as a measure of efficacy for anti-EGFR antibodies in recurrent/metastatic (R/M) squamous cell carcinoma of head and neck (SCCHN).
Authors: Krzysztof Misiukiewicz, Lewis Winder, Michael Parides, Marcelo Raul Bonomi, Marshall R. Posner
Journal: Journal of Clinical Oncology (2013)

6078 Background: Anti-epidermal growth factor receptor (EGFR) antibodies show promise in treatment of SCCHN. Since the approval of cetuximab as a first-line treatment in R/M settings, other EGFR inhibitors have failed to achieve FDA approval due to failures to achieve survival benefits, despite significant improvements in PFS. Methods: We analyzed aggregate data from all published phase III clinical trials using EGFR monoclonal antibodies as first-line treatment in R/M SCCHN, to investigate PFS as a surrogate endpoint to overall survival (OS). Results: The limited data indicate a linear relationship between PFS and OS with a constant difference between them of 5 months. This estimate has a confidence interval of variability about an estimated mean, and a prediction interval of variability around an estimate for a single patient. The meta-analyzed (fixed effect) estimate of the relative risk of mortality is 0.63 and the standard error is 0.094 and is statistically significant. Conclusions: Approval of cetuximab in SCCHN was based on significant benefit to OS observed in the Extreme study, in which controls were notably prohibited from crossover at progression. Panitumumab showed comparable benefit in PFS, though expected OS endpoints were not achieved, possibly due to over-performance of standard arms benefiting from improved second line treatment (including Cetuximab) and crossover at progression. Though not included in our analysis, Zalutumumab also showed improvement in PFS as a second line therapy. We propose that PFS be considered as a surrogate endpoint for OS in SCCHN trials, in light of new second line therapies and improved survival outcomes seen over the past decade. [Table: see text]
CA 19-9: A surrogate to assess response to treatment in patients with metastatic pancreatic cancer (MPC).
Authors: Celso L. Diaz, Pelin Cinar, Jimmy Hwang, Andrew H. Ko, Margaret A. Tempero
Journal: Journal of Clinical Oncology (2015)

e15240 Background: Changes in CA 19-9 during chemotherapy have been reported to be of prognostic importance in MPC. However, the baseline CA 19-9 that can be considered useful for evaluation of such changes has not been established. The goal of this study was to determine the threshold for baseline CA 19-9 that most closely correlates with survival benefit in patients with MPC receiving first line therapy. Methods: In this retrospective study, 228 patients with MPC were included from three clinical trials conducted at UCSF and from the UCSF cancer registry (2004-2014). CA 19-9 decline (%) was grouped into quartiles. A more detailed analysis done on patients with a baseline >1000 U/mL (n=122) included time to nadir and CA 19-9 decline at month 2 of therapy (M2). Overall survival (OS) and multivariate survival analyses were performed by the Kaplan-Meier method and Cox proportional hazards ratios (HR). Results: No significant trend in survival was observed across baseline CA 19-9 levels. Among patients with a baseline >1000 U/mL, greatest survival benefit was seen with a >75% decline to nadir. Among those with a >75% decline, 43 of 57 patients had a >50% decline at M2 and survival benefit was observed with a longer time to nadir. Small sample sizes limited analysis of other baseline groups. Conclusions: Due to small sample sizes, we were unable to determine a threshold for an evaluable baseline CA 19-9. However, for patients with a baseline >1000 U/mL, CA 19-9 decline was significantly correlated with survival benefit. Within this subgroup, we suggest that CA 19-9 can be used as a surrogate for serial imaging to evaluate treatment response. For clinical trial design, CA 19-9 decline > 75% could be used as a primary endpoint, limiting the sample size required to identify a strong clinical signal. Median OS in months (95% CI) HR (95% CI) CA19-9 Baseline < 37 38-100 101-500 501-1000 > 1000 10.38 (7.21-15.21) 15.67 (7.90-16.20) 7.14 (4.89-13.45) 8.99 (6.05-11.17) 9.65 (8.20-11.14) Ref. 1.10 (0.56–2.16) 1.99 (1.18–3.37) 2.29 (1.21–4.34) 2.26 (1.45–3.52) CA 19-9 Decline to Nadir from >1000 U/ml <25% 26-50% 51-75% >75% 5.72 (3.87-7.47) 6.68 (3.93-11.27) 8.46 (5.02-11.14) 12.23 (10.81-14.84) Ref. 0.95 (0.62-1.46) 0.96 (0.64-1.45) 0.51 (0.36-0.71)
Malignant pleural mesothelioma: A 21-year single-center experience.
Authors: Mathieu D. Saint-Pierre, Tinghua Zhang, Garth Andrew Nicholas, Scott Andrew Laurie, Paul Wheatley-Price
Journal: Journal of Clinical Oncology (2014)

7578 Background: Malignant pleural mesothelioma (MPM) is associated with a poor prognosis as most patients (pts) have advanced disease at diagnosis. Commonly used palliative chemotherapy (CT) is platinum based, and since 2004 the partner drug is usually a folate antimetabolite, either pemetrexed or raltitrexed. Selected pts presenting with early stage disease are considered for extrapleural pneumonectomy (EPP), although this approach remains controversial. We performed a single institution chart review investigating efficacy of EPP, and outcomes from CT pre- and post-2004. Methods: With ethics approval, all MPM pts from 1991 to June 2012 were identified. Data collected included age, gender, asbestos exposure, presenting symptoms, performance status (PS), histology, stage, bloodwork, treatment modalities, and date of death or last follow-up. Primary endpoint was overall survival (OS). Cox models were applied to determine variables associated with OS. Results: Of 245 identified pts, 87% were male, mean age 68 (range 21 to 88). Histology was epithelioid (63%), sarcomatoid (14%), mixed (11%) or unknown (12%). Common presentations were dyspnea (76%) and effusion (73%). Median OS for all pts was 9.4 months (mo). In univariate analysis, factors associated with shorter survival were: increasing age, poor PS, stage, sarcomatoid histology, weight loss >5%, leucocytosis (≥8.7) and thrombophilia (>400). In multivariate analysis PS, stage, histology, leucocytosis and thrombophilia remained independently associated with shorter OS. Among all pts who received CT (n=139), there was no difference in OS between the periods 1991-2004 (pre-pemetrexed) and 2004-2012 (pemetrexed era); 14.2 vs 13.2 mo (p=0.35). 20 pts underwent EPP, of which 11 had trimodality therapy with induction CT and post-op radiation. Their median OS was 24.7 vs 9.1 mo in non-EPP pts (p=0.0001). However, after multivariate analysis, the benefit of EPP was no longer statistically significant; HR 1.57, 95% CI 0.80-3.08 (p=0.19). Conclusions: In this review we did not observe an incremental improvement in survival after pemetrexed became available. Secondly, the longer OS seen in EPP pts is likely secondary to pt selection, rather than the intervention. The role of EPP remains unclear.
BTK inhibition is a potent approach to block IgE‐mediated histamine release in human basophils
Authors: D. Smiljkovic, K. Blatt, G. Stefanzl, Y. Dorofeeva, C. Skrabs, M. Focke‐Tejkl, W. R. Sperr, U. Jaeger, R. Valenta, P. Valent
Journal: Allergy (2017)

Abstract Background Recent data suggest that Bruton's tyrosine kinase ( BTK ) is an emerging therapeutic target in IgE receptor (Ig ER )‐cross‐linked basophils. Methods We examined the effects of four BTK inhibitors (ibrutinib, dasatinib, AVL ‐292, and CNX ‐774) on IgE‐dependent activation and histamine release in blood basophils obtained from allergic patients (n=11) and nonallergic donors (n=5). In addition, we examined the effects of these drugs on the growth of the human basophil cell line KU 812 and the human mast cell line HMC ‐1. Results All four BTK blockers were found to inhibit anti‐IgE‐induced histamine release from basophils in nonallergic subjects and allergen‐induced histamine liberation from basophils in allergic donors. Drug effects on allergen‐induced histamine release were dose dependent, with IC 50 values ranging between 0.001 and 0.5 μmol/L, and the following rank order of potency: ibrutinib&gt; AVL ‐292&gt;dasatinib&gt; CNX ‐774. The basophil‐targeting effect of ibrutinib was confirmed by demonstrating that IgE‐dependent histamine release in ex vivo blood basophils is largely suppressed in a leukemia patient treated with ibrutinib. Dasatinib and ibrutinib were also found to counteract anti‐IgE‐induced and allergen‐induced upregulation of CD 13, CD 63, CD 164, and CD 203c on basophils, whereas AVL ‐292 and CNX ‐774 showed no significant effects. Whereas dasatinib and CNX ‐774 were found to inhibit the growth of HMC ‐1 cells and KU 812 cells, no substantial effects were seen with ibrutinib or AVL ‐292. Conclusions BTK ‐targeting drugs are potent inhibitors of IgE‐dependent histamine release in human basophils. The clinical value of BTK inhibition in the context of allergic diseases remains to be determined.
Health-related quality of life and pain assessment in 36 patients with resected pancreas adenocarcinoma: Preliminary analysis
Authors: B. I. Carr, D. Summers, L. Menefee, S. Pierpoint, C. Yeo, E. Kennedy, H. Lavu
Journal: Journal of Clinical Oncology (2009)

e20692 Background: In order to begin to understand the effects of disease on the patient (pt) and possibly of the pt on the disease, we have begun a systematic psychological inventory of all our pts who have has a pancreatectomy for pancreas adenocarcinoma and have began to correlate this with disease extent, and later with survival. Methods: Prior to post-op discharge home, pts were invited to fill out a brief pain inventory (BPI-SF), BPI interference, emotional (EWB) and physical well-being score (Fact-Hep), as well as social/family and functional well-being (FWB) Fact-Hep. The data was entered into a database, together with pertinent lab results, tumor markers, and tumor characteristics from the pre-op CT scan and post-op pathology report. Data was analyzed by descriptive statistics, frequencies and Pearson Correlation (2-tailed sig). Results: Descriptive means (and ranges) were - tumor size 3.43 cm mean (2.0 min-5.2 max), bilirubin 1.26 (0.2–4.7), albumin 2.69 (1.5–3.6), Hb 10.3 (7.5–13.2), platelets 254K (109K-672K), CEA 4.7 (0.8–24), and Ca 19–9 was 987 (1.0–8127). Pain at presentation pre-op of moderate severity was present in 11% of pts and severe pain was present in 5.6% of pts (16.6% total). Pathologically, LNs were involved by cancer in 50% of pts, vascular invasion in 30%, neural invasion in 35% and any margin positive in 14%. 22% had metastases noted at surgery. Statistically significant correlations were found for tumor size and pain severity (p&lt;.035), platelets and FWB (p&lt;.022), albumin and Hb (p=.000), CA 19–9 and bilirubin (p&lt;.030 i.e. high CA 19–9 and high bilirubin). There was a negative correlation between CEA (but not CA 19–9) and both EWB (p&lt;.039) and FWB (p&lt;.035). Pain severity correlated with depressed mood (p&lt;.010), lower physical well-being (p&lt;.01) and interference with life activities (p&lt;.01). Conclusions: CEA, but not CA 19–9 correlated with both emotional and functional well-being. Baseline pain was present in only 16.6% of this cohort. We plan to follow up to examine how these parameters correlate with pt coping throughout therapy and survival. No significant financial relationships to disclose.
Feasibility and activity of two vinflunine (VFL)-based combinations as first-line chemotherapy (CT) in CDDP-unfit patients (pts) with advanced urothelial carcinoma (UC): VFL-gemcitabine (GEM) or VFL-CBDCA in a randomized international phase II trial (JASINT).
Authors: Maria De Santis, Pawel J. Wiechno, Christel Lucas, Wu-Chou Su, Laurence Albiges, Chia-Chi Lin, Joaquim Bellmunt, Elzbieta Senkus-Konefka, Aude Flechon, Loic Mourey, Andrea Necchi, Wolfgang C. Loidl, Maryse Morand, Jean-Philippe Burillon, Ronan Fougeray, Stephane Culine
Journal: Journal of Clinical Oncology (2014)

4534 Background: There is no standard 1st line CT for advanced or metastatic UC in patients (pts) unfit for a CDDP-based regimen. CBDCA-GEM doublet or single agents are frequently used. VFL, a novel EMA approved agent in the post-platinum setting has shown to be safe in pts with renal impairment. The aim of this study is to provide data of the benefit/risk ratio of 2 VFL-based CT regimens in UC. Methods: Pts with a creatinine clearance (CrCl) <60mL/min but ≥30, PS 0/1, no prior systemic CT (except neoadjuvant or adjuvant CT if relapse occurred ≥6 months (mo) after last dose) were randomized. Based on the CrCl, <40 or ≥40mL/min, pts received q 21 days (D) VFL 250 or 280mg/m², plus GEM (Arm A) 750mg/m² D1&8 escalated to 1000 in cycle 2 (if no toxicity Grade (G) ≥2) or plus CBDCA AUC 4.5 D1 (Arm B). The primary endpoint was the disease control rate (DCR = CR + PR + SD, RECIST 1.1). With H0=41%, H1=63%, α =5% and β =20%, 31 evaluable pts/arm were to be included to detect in each arm an improvement of 22% compared to H0. Results: 69 pts (34 arm A, 35 arm B) were enrolled 2011-2012: median follow-up 20.4 mo. Median (med) age was 70yrs, PS 0 in 42% and PS 1 in 58%; primary sites: 52% bladder and 46% upper tract; 16% had received prior CT. Pts characteristics were similar in both groups; 71% of pts had multiple comorbidities, cardiac in 23%. Med CrCl was 46mL/min (<40 in 19%). Med number of cycles was 5 [1–17] in arm A and 4 [1–11] in arm B. More haematological G3/4 adverse events (AE) were reported in arm B: neutropenia in 68% (vs 38%) and febrile neutropenia in 14% (vs 3%) of pts. Most common non-haematological G3/4 AE were fatigue (21.7%), infection (7.2%), and constipation (4.3%) without major difference between arms. DCR was similar in both groups: 76.5% (A) and 77.1% (B). ORR was confirmed in 44.1% vs 28.6%, med PFS was 5.9 vs 6.1 mo and med OS 13.9 vs 12.8 mo in arms A and B, respectively. Conclusions: This study confirms that both VFL doublets are feasible and can be administered for ≥4 cycles. The DCR was similar in both arms but haematological toxicity was more pronounced with VFL-CBDCA. Med OS warrants further study with VFL-GEM. Clinical trial information: NCT01599013.
Erratum: Corrigendum: Bone marrow stromal cells attenuate sepsis via prostaglandin E2–dependent reprogramming of host macrophages to increase their interleukin-10 production
Authors: Krisztián Németh, Asada Leelahavanichkul, Peter S T Yuen, Balázs Mayer, Alissa Parmelee, Kent Doi, Pamela G Robey, Kantima Leelahavanichkul, Beverly H Koller, Jared M Brown, Xuzhen Hu, Ivett Jelinek, Robert A Star, Éva Mezey
Journal: Nature Medicine (2009)