tbuckley/cabot-search huggingface dataset:
Lower socioeconomic classes are more exposed to air pollution in Italy
Authors: Giuseppe Verlato, Alessandro Marcon, Giang Nguyen, Simone Accordini, Pierpaolo Marchetti, Leonardo Antonicelli, Francesco Attena, Roberto Bono, Lamberto Briziarelli, Pietro Pirina, Simona Villani, Roberto de Marco
Journal: European Respiratory Journal (2012)

Objective: The present study aims at investigating whether lower socioeconomic classes, who present a higher prevalence of current smokers, are also more exposed to air pollution in Italy.  Methods: In the frame of the GEIRD study (Gene Environment Interactions in Respiratory Diseases) 10494 subjects, randomly selected from the general population aged 20-44 years in 7 centres answered a screening questionnaire between 2007 and 2010 (response percentage=57.2%). It was investigated if residential exposure to industrial plants or heavy traffic changed as a function of education or profession.  Results. Subjects with lower education were more likely to live near factories or heavy traffic roads (Table 1). Workmen presented the highest exposure to industrial plants while unemployed and housewives experienced the highest exposure to heavy traffic. In multivariable analysis profession was more associated with residential proximity to factories while education level was more associated with proximity to heavy traffic roads.  Conclusion. Lower socioeconomic classes are more exposed not only to active smoking but also to air pollution.
Objective responses in a phase I dose-escalation study of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in patients with relapsed or refractory Hodgkin lymphoma
Authors: A. Younes, A. Forero-Torres, N. L. Bartlett, J. P. Leonard, B. Rege, D. A. Kennedy, J. M. Lorenz, E. L. Sievers
Journal: Journal of Clinical Oncology (2008)

8526 Background: CD30 expression by Reed-Sternberg cells is a defining feature of Hodgkin lymphoma (HL). The ADC SGN-35 comprises an anti-CD30 antibody conjugated to monomethyl auristatin E (MMAE). SGN-35 mechanism of action involves binding to CD30 on the tumor cell surface, ADC internalization, MMAE release and binding to tubulin, prompting cell cycle arrest and apoptosis. Methods: A multicenter phase I dose escalation study was conducted in patients with refractory or recurrent CD30-positive hematologic malignancies. Twenty-nine patients (pts) were enrolled; 26 with HL, 3 with other CD30+ malignancies. Median age was 32 (range 22–87) and pts received a median of 5 prior therapies; 76% previously received an autologous stem cell transplant. Most (89%) pts had an ECOG performance status of 0/1. SGN-35 dose levels were 0.1, 0.2, 0.4, 0.6, 0.8, 1.2, 1.8 and 2.7 mg/kg (2-hr outpatient IV infusion, premedications not required) every 3 weeks (wks). Pts with stable disease or better after 2 doses were eligible to receive additional doses of SGN-35. Results: All pts were evaluable for safety, 28 pts were evaluable for response. Dose-limiting toxicity was not defined and 1 infusion-related reaction was observed. One pt (0.1 mg/kg) experienced G3 hypercalcemia and 1 pt (1.8 mg/kg) had G4 thrombocytopenia (both reversible and possibly related). One pt (0.4 mg/kg) experienced a possibly related myocardial infarction that resolved without sequalae. The most common related adverse events were G1/2 fatigue, diarrhea and cough. Pharmacokinetic data indicate exposure (AUC) to SGN-35 increased relative to dose level, with no accumulation after repeated dosing. Best response: partial remission (n=9), stable disease (n=11), and progressive disease (n=8). At dose levels of ≥1.2 mg/kg, 7 of 13 pts (54%) achieved PR and remain on therapy at 11+ to 25+ wks; tumor reductions occurred in 11 of 13 pts. Enrollment continues at 2.7 mg/kg. Conclusions: SGN-35, a novel ADC targeting CD30, was generally well tolerated at doses up to 2.7 mg/kg, and induced multiple objective responses in heavily pretreated pts. These encouraging results indicate SGN-35 should be further evaluated in phase II studies for pts with HL. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Seattle Genetics, Inc Seattle Genetics, Inc Seattle Genetics, Inc
Exon-Based Transcriptome Profiling Reveals Genes That Have Prognostic Impact on the Survival of Young High Risk Diffuse Large B-Cell/Follicular Grade 3 Lymphoma Patients Treated with Dose-Dense Chemoimmunotherapy and CNS Prophylaxis. Results From a Nordic Lymphoma Group Phase II Study
Authors: Satu Koivula, Minna Taskinen, Ping Chen, Harald Holte, Jan Delabie, Marja-Liisa Karjalainen-Lindsberg, Magnus Bjorkholm, Oystein Fluge, Lars Moller Pedersen, Mats Jerkeman, Mikael Eriksson, Sampsa Hautaniemi, Sirpa Leppa
Journal: Blood (2010)
Safety in patients receiving maintenance rituximab for follicular lymphoma: Results from the phase IIIb MAXIMA trial
Authors: M. K. Wenger, R. Foa, L. Arcaini, A. Vranovský, V. Ivanova, G. A. Van Hazel, S. Kurtovic, S. Durán, E. Gamba, D. Thurley
Journal: Journal of Clinical Oncology (2008)

8606 Background: The clinical benenfit of improved PFS and OS for rituximab maintenance in follicular lymphoma (FL) has been reported in five randomized trials. The primary objective of the current study is to extend the safety database for rituximab maintenance following a wide range of induction therapies. The study also examines the safety profile associated with rapid-infusion of rituximab. Methods: The sample size of this single-arm trial has been calculated to detect at least one rare event with a true incidence of 0.32% with 80% power. Patients with first line or relapsed/refractory FL achieving a response after rituximab containing induction therapy were eligible to receive rituximab at the standard dose for follicular lymphoma of 375 mg/m2 every eight weeks for a maximum of 2 years. Primary endpoint is safety, with secondary endpoints being PFS, EFS, TTNL, and OS. Results: 349 patients with FL have been enrolled at clinical cut-off for whom demographic data is available: Median age of the patient population is 56 years [range: 29 to 82], with 47% being male. Seventy-six per-cent of patients had their first lymphoma treatment prior to enrollment, while the remaining 24% of patients had up to 4 previous treatments; 74% entered the study in CR/CRu. Data on a total of 809 infusions was available. Except for one patient who received rituximab at standard infusion speed and suffered from a TIA no SAEs were recorded within 24h of the maitenance infusion, including those patients who received rituximab via a rapid infusion protocol. A total of 9 SAEs were recorded in the 275 patients that received at least one infusion, all but one were considered unrelated. One patient with previously known cardiac arrythmias died 13 days after the 4th infusion of unknown causes. After clinical cut-off, another patient died of progressive lymphoma. Hematologic toxicity occured in 9 patients, with three grade 3/4 events (neutropenia), one resulting in febrile neutropenia. Data on efficicacy will be presented. Conclusions: Rituximab maintenance q 8 weeks in FL after rituximab containing induction therapy can be safely administered, regardless if a rapid-infusion protocol is used or not. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche Roche
Cutaneous side effects (cAE) of vemurafenib (V): Single-center cohort study of 28 metastatic melanoma (mM) patients (pts).
Authors: Simone M. Goldinger, Jeannine Desiree Rinderknecht, Benedetta Belloni, Nina Eggmann, Reinhard Dummer
Journal: Journal of Clinical Oncology (2012)

e19017 Background: V is a potent BRAF inhibitor with significant impact on progression-free and overall survival in mM pts. cAE are very common. This single-center observation analyses the clinical and histological spectrum of this new class-specific cAE in 28 pts treated with V in different clinical trials. Methods: 28 mM pts stage IV were treated with V 960mg b.i.d. in local ethic committees approved clinical trials. Occurring side effects were collected and documented prospectively. 65 biopsies were analysed. cAE were classified by reaction pattern as inflammatory diseases, hair and nail changes, keratinocytic proliferations, melanocytic disorders and proliferations. Results: V was well tolerated; in 2 pts dose reduction was necessary due to arthragia. 26/28 pts (93%) experienced cAE. UVA dependent photosensitivity and maculopapular exanthema were observed in 16 and 14 pts respectively. The histology of the rash demonstrated alteration of eccrine and follicular structures with mild inflammation and no increased keratinocytic apoptosis, thus differing from the rash of MEK inhibitors. Pruritus was observed in 8, folliculitis in 5, and burning feet in 3 pts. Hair thinning and alopecia occurred in 8 pts, 2 pts presented with curly hair. Follicular hyperkeratosis and acanthopapilloma were common skin reactions (n=12/n=13), as well as plantar hyperkeratosis (n=4), keratoacanthoma (n=5) and invasive squamous cell carcinoma (n=4). Histology of the acanthopapilloma (n=39) showed marked hyperkeratosis and acanthosis with koilocytes and mitosis, suggesting viral association. Single observations of morbus Bowen, Bowen carcinoma, basal cell carcinoma and a warty dyskeratoma were documented. 1 pt developed after more than 4 months of therapy a secondary primary melanoma on the capillitium (BRAF and RAS wildtype). Conclusions: V has a broad and particular cAE profile involving epidermis and adnexals. Regular skin examination by experienced dermatologists is crucial under V to detect and treat the possible side effects promptly. The treatment is very well tolerated but can have an impact in quality of life; ergo the pts have to be well informed. UVA optimized photoprotection is essential.
A prospective study of carboplatin-etoposide in docetaxel-pretreated patients with hormone-refractory prostate cancer (HRPC): Clinical activity and correlation with neuroendocrine features
Authors: Y. Loriot, C. Massard, A. Plantade, B. Escudier, A. Chauchereau, R. De Crevoisier, K. Fizazi
Journal: Journal of Clinical Oncology (2007)

5151 Background: There is currently no standard of care for patients (pts) with HRPC and disease progression after docetaxel-based chemotherapy. Platin compounds have demonstrated activity in this setting and in vitro evidence of synergy between carboplatin and etoposide has previously been reported. A significant proportion of advanced HRPC exhibit neuroendocrine features but there are limited data on whether these patients should be treated differently or not. Methods: Pts with HRPC who experienced failure after first-line docetaxel-based chemotherapy were prospectively treated with carboplatin (AUC 5 day 1) and etoposide (80 mg/m 2 day 1 to 3), repeated every 3 weeks as second-line chemotherapy. The response rate (defined as a serum PSA decline of = 50%), progression-free survival (PFS) and overall survival (OS) were evaluated using consensus criteria (Bubley JCO 1999). Pain relief was evaluated using a visual analogic scale. Serum chromogranin A and neurone specific enolase (NSE) levels were measured at baseline. Toxicity was evaluated according to NCI criteria. Results: Forty-one HRPC pts, previously treated with docetaxel with (n=24) or without (n=17) estramustine, prospectively received carboplatin-etoposide as second-line chemotherapy. A PSA response was obtained in 9 pts (22%). Pain relief was achieved in 18 pts (45%). Median progression-free survival was 9 weeks and median overall survival was 19 months. Toxicity included grade 3–4 anemia in 25% and febrile neutropenia in 2%. Biological neuroendocrine features (e.g. elevated baseline serum chromogranin A and NSE) were not associated with response or PFS. The response rate was 18% and 31% in pts with normal and elevated baseline chromogranin A, respectively. Conclusions: The carboplatin-etoposide regimen is active and well-tolerated as second-line chemotherapy after docetaxel-based chemotherapy in HRPC patients. Activity was detected in both tumors with and without neuroendocrine features. No significant financial relationships to disclose.
Abstract 333: Deficiency of DJ-1 Leads to Increased Injury following Myocardial Ischemia by Enhancing Apoptosis and Oxidative Stress
Authors: Jonathan P Lambert, Chad K Nicholson, John W Calvert
Journal: Circulation Research (2013)

Background: DJ-1 is a ubiquitously expressed protein that has typically been associated with the development of early onset Parkinson’s disease. Recent data suggests that it also plays a role in the cellular response to stress. Although much is known about DJ-1 in the brain, very little has been investigated in the heart. Here, we tested the hypothesis that a deficiency in DJ-1 would enhance myocardial ischemia-reperfusion (MI/R) injury. Methods and Results: Wild-type (WT) control and DJ-1 knockout (DJ-1 KO) mice were subjected to 45 min of left coronary artery ischemia followed by 24 hrs of reperfusion. The deficiency of DJ-1 significantly increased myocardial infarct size relative to both the area-at-risk and entire left ventricle, as well as increased circulating troponin-I levels (Panels A-B). Echocardiography and hemodynamic analysis at 1 week of reperfusion revealed that DJ-1 KO mice experienced greater left ventricular dilatation and hypertrophy, displayed exacerbated left ventricular dysfunction, and displayed worse contractility and relaxation when compared to WT controls. In an effort to evaluate the signaling mechanism responsible for the increased injury in DJ-1 KO mice, additional WT and KO animals were subjected to 45 min of ischemia followed by 4 hrs of reperfusion. DJ-1 KO hearts were found to display higher levels of oxidative stress, greater caspase-3 activity (Panel C), enhanced phosphorylation of Jnk, and enhanced activation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1). Conclusions: These findings provide important information that DJ-1 plays a protective role in heart against acute MI/R injury.
Head and neck squamous cell carcinoma in patients over 80 years old: patterns of care and survival
Authors: C. Ortholan, A. Italiano, O. Dassonville, G. Poissonnet, J. Thariat, K. Benezery, J. Vallicioni, F. Peyrade, A. Thyss, P. Y. MARCY, R. J. Bensadoun
Journal: Journal of Clinical Oncology (2008)

6050 Background: Scarce data exist concerning the outcome of elderly patients (pts) diagnosed with head and neck squamous cell carcinoma (HNSCC). Methods: We reviewed clinical files of 316 HNSCC pts aged 80 years recorded in our institution database between 1987 and 2006. Results: 316 pts were included in the study. Distribution of tumor site was: oral cavity 145 (46%), larynx 73 (23%), oropharynx 61 (26%), salivary gland 14 (5%), hypopharynx 13 (4%), paranasal sinus and nasopharynx 10 (3%). Sex ratio for oral cavity location was 0.46 and 23% of these tumors were related to traumatic oral lesion or leukoplakia. 114 pts (36%) had stage I/II disease and 202 (64%) stage III/IV disease. 277 pts (88%) received a locoregional treatment (LRT) (97% of stage I/II and 82% of stage III/IV). The intent of LRT was curative in 215 (68%) pts (92% of stage I/II and 54% of stage III/IV) and palliative in 62 (20%) pts (5% of stage I/II and 28% of stage III/IV). Palliative pts were older (> 85 years), in poorer general status (PS≥ 2) and had more comorbidities (≥ 3) than curative pts (P = 0,01; P < 0,0001; P < 0,0001, respectively). 159 pts (50%) were curable by surgery. Among them, 97 pts (61%) had effectively surgical resection of the primary tumor. Adjuvant radiotherapy (RTH) after surgery was indicated in 59 pts. 34 pts (58%) effectively received adjuvant RTH. 180 pts (57%) were treated with definitive RTH. 65 pts (40%) received a conventionally fractionated regimen, with a median dose on the primary site of 66 Gy (range 8–70 Gy). 91 pts (56%) received an adapted hypofractionated/split course schedule. Patterns of survival are described in the table. On multivariate analysis, independent predictors of improved disease specific and overall survival were stage I/II, curative intent of LRT and evidence of locoregional control. Conclusion: The outcome of HNSCC pts ≥ 80 years with localized disease is similar to that of younger patients whereas those with regionally advance disease have a poorer survival as the result of a frequent suboptimal treatment. Significant Prognostic Factors on Specific and Overall Survival (multivariate analysis) Variable Specific Survival Overall survival Median (Months) Hazard Ratio p value Median (Months) Hazard Ratio p value Whole population 21.3 — — 13.0 — — Stage Stage I/II Not reached 0.52 [0.07-0.96] p = 0.004 41.9 0.59 [0.28-0.90] p = 0.001 Stage III/IV 11.4 1 7.9 1 Intent of treatment Curative 67.1 0.45 [0.02-0.87] p = 0.001 24.5 0.49 [0.17-0.89] p = 0.001 Palliative/No treatment 4.0 1 3.8 1 Locoregional control Yes Not reached 0.26 [0-0.68] p <0.0001 30.0 0.57 [0.22-0.92] p = 0.002 No 11.4 1 10.5 1 No significant financial relationships to disclose.
Evaluation of TCR Gene Editing Achieved by TALENs, CRISPR/Cas9, and megaTAL Nucleases
Authors: Mark J Osborn, Beau R Webber, Friederike Knipping, Cara-lin Lonetree, Nicole Tennis, Anthony P DeFeo, Amber N McElroy, Colby G Starker, Catherine Lee, Sarah Merkel, Troy C Lund, Karen S Kelly-Spratt, Michael C Jensen, Daniel F Voytas, Christof von Kalle, Manfred Schmidt, Richard Gabriel, Keli L Hippen, Jeffrey S Miller, Andrew M Scharenberg, Jakub Tolar, Bruce R Blazar
Journal: Molecular Therapy (2015)

Present adoptive immunotherapy strategies are based on the re-targeting of autologous T-cells to recognize tumor antigens. As T-cell properties may vary significantly between patients, this approach can result in significant variability in cell potency that may affect therapeutic outcome. More consistent results could be achieved by generating allogeneic cells from healthy donors. An impediment to such an approach is the endogenous T-cell receptors present on T-cells, which have the potential to direct dangerous off-tumor antihost reactivity. To address these limitations, we assessed the ability of three different TCR-α-targeted nucleases to disrupt T-cell receptor expression in primary human T-cells. We optimized the conditions for the delivery of each reagent and assessed off-target cleavage. The megaTAL and CRISPR/Cas9 reagents exhibited the highest disruption efficiency combined with low levels of toxicity and off-target cleavage, and we used them for a translatable manufacturing process to produce safe cellular substrates for next-generation immunotherapies. Present adoptive immunotherapy strategies are based on the re-targeting of autologous T-cells to recognize tumor antigens. As T-cell properties may vary significantly between patients, this approach can result in significant variability in cell potency that may affect therapeutic outcome. More consistent results could be achieved by generating allogeneic cells from healthy donors. An impediment to such an approach is the endogenous T-cell receptors present on T-cells, which have the potential to direct dangerous off-tumor antihost reactivity. To address these limitations, we assessed the ability of three different TCR-α-targeted nucleases to disrupt T-cell receptor expression in primary human T-cells. We optimized the conditions for the delivery of each reagent and assessed off-target cleavage. The megaTAL and CRISPR/Cas9 reagents exhibited the highest disruption efficiency combined with low levels of toxicity and off-target cleavage, and we used them for a translatable manufacturing process to produce safe cellular substrates for next-generation immunotherapies.
CALGB 30103: A randomized phase II study of carboplatin and etoposide (CE) with or without G3139 in patients with extensive stage small cell lung cancer (ES-SCLC)
Authors: C. M. Rudin, R. Salgia, X. F. Wang, M. R. Green, E. E. Vokes
Journal: Journal of Clinical Oncology (2005)

7168 Background: Bcl-2, an inhibitor of apoptosis associated with chemotherapeutic resistance, is expressed in up to 90% of SCLC. The antisense oligonucleotide G3139 can suppress Bcl-2 levels and increases chemotherapeutic efficacy in preclinical models. A prior phase I clinical trial defined a regimen combining G3139 with CE in patients with ES-SCLC with acceptable toxicity. Methods: This was a two-arm phase II study using 3:1 randomization to CE with (arm A) or without (arm B) G3139 in adults with previously untreated ES-SCLC and ECOG performance status 0–2. Objectives included assessment of % of subjects alive after 12 months, response rate, and toxicity in arm A, as well as comparison of toxicity between arms. Results: Accrual from 7/03 to 10/04 was 63 patients with 47 in arm A and 16 in arm B. Four patients in arm A canceled registration before treatment and are excluded from analysis. Study arms were well balanced for age, gender, race, ethnicity, and performance status. Of 18 patients on arm A currently evaluable for response, objective response was seen in 67% (6% CR, 61% PR). As of 11/24/04, adverse event data were available for 28 patients in arm A and 5 in arm B. There have been 12 deaths on study, 10 in arm A. One death in arm A was due to renal failure and is considered probably treatment related. There is a trend toward increased grade 4+ toxicity in arm A (17/28=61%) compared to arm B (2/5=40%), p=0.11. Most common grade 4 toxicities included neutropenia (43%), thrombocytopenia (14%), and leukopenia(14%). Non-hematologic toxicities were rare. Median follow-up is insufficient to estimate survival time on either arm. Conclusions: Co-administration of G3139 with CE for ES-SCLC is feasible in a multi-institutional context, but may be associated with increased toxicity. Final analysis of adverse events and clinical outcome data, especially survival time, from this study will help define whether this toxicity is counterbalanced by patient benefit. No significant financial relationships to disclose.
Abstract 13201: Evaluation of a New High Resolution 4D Echo Based Motion Analysis Program for RV Strain Computation
Authors: Zhijun Zhang, Xubo Song, Muhammad Ashraf, Meihua Zhu, Cole Streiff, David J Sahn
Journal: Circulation (2012)

Background: Thin right ventricular (RV) walls and the unique geometry of the RV present challenges in image based evaluation of RV function. We tested the feasibility of a new high resolution DENSE motion analysis program for RV strain computation using full volume 4D image loops. Methods: Five open chest instrumented pigs were studied under different steady states. Three sonomicrometry crystals were implanted on the RV surface. After acquiring baseline image data, each pig was subjected to epicardial pacing from different ventricular sites (RV, RV outflow tract, left ventricle [LV] and RV apex) allowing compete recovery to regain sinus rhythm after each pacing state. Full volume 4D image loops were acquired at each state with an X7-2 matrix probe on a Phillips IE33 ultrasound system at a frame rate >25 directly from the surface of the heart. Image data was analyzed in an offline high resolution MatLab based motion analysis program for RV strain. Results: At each state sonomicrometry derived strain values...