tbuckley/cabot-search huggingface dataset:
Abstract 17028: Genetically-Programmed Suicide of Adrenergic Cells in Mice Produces Left Ventricular Dysfunction as Revealed by High-Resolution Echocardiography
Authors: Aaron P Owji, Candice N Baker, Jeffrey L Jacob, Steven N Ebert
Journal: Circulation (2014)

The enzyme Phenylethanolamine-N-methyltransferase (Pnmt), which catalyzes the conversion of norepinephrine into epinephrine, serves as a marker for adrenergic cells and is expressed in the developing heart. In the present study, we tested the hypothesis that adrenergic cells play an important role in the development of cardiac function by assessing phenotypes of mice with selective ablation of adrenergic cells compared with littermate controls. Briefly, Pnmt-Cre knock-in mice were crossed with ROSA26-eGFP-DTA mice, which results in selective ablation of Pnmt+ adrenergic cells due to activation of the Diphtheria Toxin Alpha (DTA) “suicide” allele from the ROSA26 locus. Control experiments verified that the model was working correctly since Pnmt-Cre/DTA mice had markedly lower Pnmt mRNA (>97% decrease) and fewer Pnmt+ cells (>50% decrease) in adrenal glands compared to littermate controls. Pnmt-Cre/DTA mice were born in normal Mendelian ratios and appeared outwardly normal and healthy at birth and during the early postnatal period, but began to show cardiac deficits by one month of age. High-resolution echocardiography analysis indicated continuing deterioration of cardiac function with age. Mean cardiac output was decreased at four months (10.81±2.73 mL/min n=14 v 18.42±3.37 mL/min n=18, p-value<0.001, Fig. 1), as was ejection fraction (54.34±7.44% v 66.53±8.51%, p<0.01), and fractional shortening (27.64±4.80% v 36.67±7.22%, p<0.01). Moreover, left ventricular function was hypokinetic in the ablated hearts compared to controls, as shown in the M-mode tracings in Fig. 1. These data demonstrate that selective ablation of adrenergic cells leads to impaired cardiac function that progressively worsens with age over the first few months after birth. In conclusion, this novel cellular suicide model is useful for determining how adrenergic cells contribute to the development of cardiac structure and function.

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Phase I dose-escalation study of oral vinflunine given twice a day for 2 consecutive days every week in patients with solid tumours
Authors: J. Bennouna, J. B. Vermorken, H. Senellart, C. Valverde, S. Altintas, V. Aslanis, M. Brandely, E. Calvo-Aller
Journal: Journal of Clinical Oncology (2008)

13555 Background: Vinflunine (VFL) is a new microtubule inhibitor of the vinca-alkaloid family undergoing phase III development as 20 minute infusion given every 3 weeks. I.V VFL displays dose proportional pharmacokinetics (PK) with a terminal half-life of about 40 hours. Hard capsules have been devised to explore repeated, oral administrations of VFL. Absolute bioavailability of this oral form was 57.3% with limited inter-individual variability (CV = 19%) (AACR-NCI-EORTC 2007, abstract 90). Methods: A phase I study has been conducted to determine the maximal tolerated dose (MTD) and PK of oral VFL given twice a day after breakfast and dinner on days 1–2 every week, with 3 weeks cycles. A flat-fixed dosing was used given the absence of correlation between total clearance of VFL and body surface area. Results: 20 patients (pts) have been treated at 4 dose levels (DL) so far = 150 (3 pts), 190 (3 pts), 230 (8 pts), 300 (6 pts) mg/day. At 300 mg/day, 2 patients experienced febrile neutropenia concomitant with grade 3 diarrhoea during cycle 1 which led to consider this DL as the MTD. The number of pts in the previous DL of 230 mg/day was expanded up to 8 pts (2 non evaluable pts). Only one out of the 6 evaluable pts at this DL experienced grade 3 nausea and vomiting during cycle 1. The most common drug-related adverse events occuring at any cycle included anaemia (89% of pts) already present at baseline in about half of pts, neutropenia (25% of pts), nausea (56%) and asthenia/fatigue (44%). At the time of writing they were grade 1 or 2 (NCI v3). No VFL blood accumulation was observed between weeks, but slight and predictable accumulation of VFL and its metabolite DVFL occurred over the 4 consecutive administrations per week. So far, 2 pts had stable disease > 3 months = one thyroid carcinoma, one non-small cell lung cancer. Conclusions: Repeated, weekly administration of oral vinflunine is feasible, the MTD being reached at 300 mg/day given for 2 consecutive days. Additional patients are currently being enrolled to better define the recommended dose. No significant financial relationships to disclose.
Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study)
Authors: Yuko Kaneko, Tatsuya Atsumi, Yoshiya Tanaka, Masayuki Inoo, Hitomi Kobayashi-Haraoka, Koichi Amano, Masayuki Miyata, Yohko Murakawa, Hidekata Yasuoka, Shintaro Hirata, Hayato Nagasawa, Eiichi Tanaka, Nobuyuki Miyasaka, Hisashi Yamanaka, Kazuhiko Yamamoto, Tsutomu Takeuchi
Journal: Annals of the Rheumatic Diseases (2016)

Objective To compare the efficacy and safety between tocilizumab added to methotrexate and tocilizumab switched from methotrexate in patients with active rheumatoid arthritis (RA). Methods This is a 2-year randomised, controlled study. RA patients with moderate or high disease activity despite methotrexate were randomly assigned either to tocilizumab added to methotrexate (add-on) or tocilizumab switched from methotrexate (switch). The primary endpoint was the DAS28 remission rate at week 24. Secondary objectives included other clinical efficacy indices, radiological outcomes assessed with the van der Heijde-modified total Sharp scoring system (mTSS), and safety. Results Of 223 randomised patients, 83% completed 52 weeks. DAS28 remission rates at week 24 were 70% for add-on and 55% for switch (p=0.02), but they became comparable at week 52 (72% vs 70%, p=0.86). Structural remission rates (mTSS≤0.5) at week 52 were not different (66% vs 64%, p=0.92). However, clinically relevant radiographic progression rates (CRRP; mTSS≥3) tended to be higher with the switch than with the add-on (15% vs 7%, p=0.07). Radiographic progression in the CRRP patients was larger with the switch than with the add-on (9.0/year vs 5.0/year, p=0.04). The difference in the mean C-reactive protein of the CRRP patients was significant for the first 24 weeks (1.56 vs 0.49, p=0.001) but not for the following 28 weeks (0.10 vs 0.04, p=0.1). Overall safety was preferable in the switch group. Conclusions In RA patients with inadequate response to methotrexate, tocilizumab added to methotrexate more rapidly suppressed inflammation than tocilizumab switched from methotrexate, leading to superior clinical efficacy and prevention of joint destruction. Trial registration number NCT01120366.
Safety and Efficacy Of BEZ235, a Dual PI3-Kinase /mTOR Inhibitor, In Adult Patients With Relapsed Or Refractory Acute Leukemia: Results Of a Phase I Study
Authors: Lydia Wunderle, Susanne Badura, Fabian Lang, Andrea Wolf, Eberhard Schleyer, Hubert Serve, Nicola Goekbuget, Heike Pfeifer, Gesine Bug, Oliver G. Ottmann
Journal: Blood (2013)
Multiple primary cancers involving nonbreast sites.
Authors: L. S. Maddali, S. Maddali
Journal: Journal of Clinical Oncology (2010)

e12033 Background: Statistics of Multiple Primary Cancers (MPC) are dominated by Breast Cancer. A study of MPC involving non-breast sites might highlight subsets with special features. Methods: Between 1 January 1999 and 31 December 2009 we encountered 177 patients with MPC among a total of 5481 cases. Out of these 97 cases involving non-breast sites only were studied. Analysis was done with respect to sex, synchronous (sync) versus metachronous (meta), age groups- I: 20 to 39 yrs; II: 40-59 yrs; III: 60 yrs and above; Combinations: solid- solid neoplasms (SS), solid- hematologic neoplasms (SH), hematologic - hematologic neoplasms (HH). Results: Males: 58 (59.79%) female: 39 ( 40.21%) synchronous 28 (28.37%) metachronous 69 (71.13%) , age groups I 08 (8.25%) II 28 (28.86%) III 61 (62.89%) combinations of neoplasms SS: 69 (71.14%) SH 24 (24.74%) HH: 04 (4.12%). Top 5 Subsets: 72 (74.23%) SS/meta/male 25 (25.77% ) SS/meta/female 22 (22.68%) SS/sync/male 10 (10.31%) SH/meta/male 09 (9.28%) SH/sync/male 06 (6.19%) Other subsets < 3 (3.09%) each. Conclusions: Our Cohort of MPC involving non-breast sites showed preponderance of male sex, metachronous neoplasms, age group III, SS neoplasms. Top 5 common solid neoplasms were: gastrointestinal, urologic, lung, gynecologic and head and neck cancer (HNSCC). Top 2 hematologic neoplasms: CLL and multiple myeloma. Metachronous SS Neoplasms were increased in II and III age groups in both sexes. Synchronous SS, both synchronous and metachronous SH groups were increased in males, age group III only. Urologic (76.92%), gynecologic (75.00%), HNSCC (75.00%), were Index neoplasms, lung tumors were second primary neoplasms (94.74%).Gastrointestinal tumors were equally distributed (Index tumors 51.72%). Multiple myeloma was associated with synchronous MPC and CLL with metachronous MPC. No significant financial relationships to disclose.
Prognostic implication of smoking history in patients with non-small cell lung cancer (NSCLC)
Authors: I. Oze, Y. Segawa, N. Nogami, E. Komori, S. Sawada, M. Yamashita, T. Shinkai
Journal: Journal of Clinical Oncology (2007)

7699 Background: The AJCC disease stage, performance status (PS), and weight loss are established and important prognostic factors in patients with NSCLC. However, it is controversial whether smoking history affects the prognosis or not. We therefore assessed prognostic implication of smoking in patients with NSCLC. Methods: This retrospective study was performed using an institutional database for 1,440 NSCLC patients between 1995 and 2005. The characteristics of these patients were as follows: median age, 68 years (range,19–93); male/female, 947/493 patients; smokers/never-smokers, 897/543 patients; ECOG PS 0–1/2–4, 1319/121 patients; AJCC disease stage I-II/III-IV, 715/725 patients; squamous cell/non-squamous cell histologies, 391/1,049 patients; and weight loss &gt; 5%/0–5%, 229/1,211 patients. Results: At a median follow-up time of 17 months (range, 1–59.7 months), the median survival time in smokers was 25 months, and significantly shorter than that in never-smokers (52 months, P &lt; 0.0001). In a multivariate analysis using a Cox regression model, significance of the risk of death in smoking was confirmed when adjusted for age, sex, AJCC disease stage, ECOG PS, weight loss, and histologic subtypes (HR = 1.227, 95% CI 1.018–1.478, P = 0.032). Conclusions: Smoking history was considered to be a possible prognostic factor in patients with NSCLC. No significant financial relationships to disclose.
Phase Ib study of CP-868,596, a PDGFR inhibitor, in combination with docetaxel (Doc) with or without AG-013736, a VEGF inhibitor
Authors: M. Michael, G. Vlahovic, K. Khamly, K. J. Pierce, F. Guo, A. J. Olszanski
Journal: Journal of Clinical Oncology (2008)

3549 Background: CP-868,596 (CP) is a specific inhibitor of the platelet-derived growth factor receptors (PDGFR) and axitinib (AG) is a specific inhibitor of vascular endothelial growth factor receptor (VEGFR) tyrosine kinases. Both PDGF and VEGF have been implicated in tumor growth and chemotherapy resistance. The primary objective of this study was to assess the safety and tolerability of CP ± AG in combination with Doc. Methods: Cohorts 1–3: Dose escalation of CP given orally, BID in combination with Doc in 21 day cycles. Cohort 4: CP BID + AG 5 mg BID in combination with Doc. Each cohort consisted of a specific lead-in phase for 21 days (cohorts 1–3) or 7 days (cohort 4) wherein patients received 100 mg BID of CP given on an empty stomach over 14 days, followed by a cohort dose (60 or 100 mg BID given with food) for 7 days or 60 mg BID of CP and 5 mg BID of AG for 7 days, respectively. After the lead-in phase, Doc (75 mg/m2 or 100 mg/m2 IV) was administered. PK samples for each patient were collected for CP only or CP + AG and for CP ± AG and Doc. PK parameters were estimated by non compartmental techniques. Results: 47 pts with solid tumors were treated with demographics M:F = 36:11; 96% Caucasian, median age 57 (range 25–78); PS 0–1 96%. AEs possibly related to CP and/or AG included nausea, diarrhea, vomiting, anemia, lethargy, stomatitis, neutropenia, anorexia, peripheral edema and hypertension. AEs were generally CTC grade 1–2 and reversible. Secondary to an apparent increased incidence of stomatitis and neutropenia, escalations of CP + AG were not attempted. DLTs included febrile neutropenia, and nausea and vomiting. Cmax and AUC0–12hr of CP (n=11) were not different when administered at 100 mg BID with food either as a single agent or combined with Doc (75 mg/m2). Evidence of antitumor activity was observed, most notably in the CP + AG cohort (N=9), with a median duration on study of 4.7 months (range 2–5.4 months). Conclusions: CP at the RP2D of 100 mg BID can be combined with Doc at both 75 and 100 mg/m2 and CP 60 mg BID + AG 5 BID mg can be combined with Doc at 75 mg/m2. The tested regimens were tolerable. PK interactions between CP ± AG and Doc was not evident in the preliminary analysis. Anti-tumor activity was observed. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology
Neoadjuvant paclitaxel (P), carboplatin (Ca) and gemcitabine (G) in patients with locally advanced transitional cell carcinoma (TCC) of the bladder: A final report
Authors: D. C. Smith, N. J. Mackler, M. H. Hussain, R. Dunn, J. E. Montie, D. Wood, C. T. Lee, D. Petrylak, D. Quinn, U. Vaishampayan
Journal: Journal of Clinical Oncology (2006)

4541 Background: PCaG has activity in the treatment of TCC. Studies have shown that neoadjuvant chemotherapy may improve survival in TCC, with pathologic complete responders (pT0) having the most benefit. This study was designed to assess the pT0 rate and resectability following neoadjuvant PCaG in patients with TCC of the bladder. Methods: Patients with adequate organ function, performance status 0–2, and clinical T3 or T2 with hydronephrosis, N0, M0 TCC (Arm I) received 3 cycles of PCaG (P: 200 mg/m 2 , IV over 3 hours day 1, C: target AUC=5 IV day 1, and G: 800 mg/m 2 ; IV day 1 &amp; 8 every 21 days) followed by cystectomy with a primary endpoint of pT0. T4 or node positive (Tany, N1–3, M0) patients (Arm II) received 6 cycles with an endpoint of resectability. Each arm had a Minimax two-stage accrual with planned initial enrollment of 26 evaluable subjects in arm I (up to 54 total) and 19 in arm II (up to 33). Results: 68 patients were registered (31 arm I, 37 arm II). Median age was 65 years in arm I and 58 years in arm II. 22/31 (71%) patients in arm I are evaluable and 7 were pT0 at cystectomy. pT0 rate is 32% (95% CI: 13.9–54.9%) of evaluable, 23% (9.6–41.1%) by intent to treat (ITT). 30/37 (81%) on arm II are evaluable for response and 20 had cystectomy for a resection rate of 67% (47.2–82.7%) of evaluable, 54% (36.9–70.5%) by ITT. 5 patients resected on arm II had pT0 and 2 had only residual carcinoma in situ. A total of 252 cycles of therapy were delivered (80 in arm I, 172 in arm II) with 161 at full dose. 54/68 patients (79%) had grade 3/4 hematologic toxicity, primarily neutropenia with 4 other episodes of grade 3 toxicity (2-neuropathy, 1-myalgia, 1-fatigue). 4 patients died during chemotherapy (2-bowel obstruction, 1-coronary artery disease, 1-intracranial bleed) and 2 post-op (1-multiorgan failure, 1-enterocolitis). Only 1 death was clearly chemotherapy related, but the study was halted early due to these deaths. Conclusions: Neoadjuvant PCaG has demonstrated activity in locally advanced TCC of the bladder, but has considerable toxicity. The pT0 rate with this combination is comparable to the rates reported in the literature for other regimens. Support from Bristol-Myers Squibb, Eli Lilly, and 2P30 CA 46592–14 from the National Cancer Institute [Table: see text]
Abstract 19465: QRS Scoring System for Early Estimation of Myocardial Infarct Size and Its Ability to Accurately Predict Ejection Fraction at 3 Months and the Need for Early AICD Implantation
Authors: Jorge Romero, Rodolfo A Estrada, Nidhish Tiwari, Anthony A Holmes, Akbar Ahmed, Eric Manheimer, Mario J Garcia
Journal: Circulation (2014)

Background: Given the existing controversy regarding the appropriate determination time for placement of implantable cardioverter-defibrillator (ICD) in patients at risk for sudden cardiac death (SCD) following acute myocardial infarction (AMI) and because of the fact that the highest incidence of SCD occurs in the first 3 months after an event. We proposed to evaluate whether quantification of left ventricular (LV) scar size shortly after AMI using the well validated Selvester QRS score strongly correlates with ejection fraction at 3 months. Methods: A total of 28 consecutive post-AMI patients were included in this study. All patients had STEMI and underwent cardiac catheterization. EKGs before discharge were analyzed to calculate QRS score (32 criteria). We used adjusted criteria for each of the following abnormalities: left and right ventricular hypertrophy (LVH and RVH, respectively), left anterior fascicular block (LAFB), left bundle-branch block (LBBB), right bundle-branch block (RBBB), RBBB + LAFB,...
Abstract 17099: Hyperuricemia Could Predict Resistance in Weight Loss and Weight Loss-induced BP reduction Associated With Sympathetic Activation
Authors: Kazuko Masuo
Journal: Circulation (2014)

Introduction: Hyperuricemia (hyperUA) is a cardiovascular risk and uric acid (UA) levels may predict future hypertension. In this study, we evaluated the relationships between UA levels and future weight loss (WL) and blood pressure (BP) reduction with WL regimens, and the mechanism of chronic WL on UA levels. Methods: Obese, mild hypertensive men (n=154) on no medications were measured BMI, blood pressures (BP), UA, fasting glucose, plasma norepinephrine (NE), insulin (INS) and HOMA-IR before and every 6 month over 2 yrs with WL regimens (mild cadiet + exercise). Significant WL was defined as ≥10% WL of entry BMI at 2 yrs. HyperUA was defined as >mean+1SD (4.3 + 1.5 mg/dL). Results: Significant WL was observed in 47.8% at 1 yr and 61.7% at 2 yrs. HyperUA was noted in 64.3% at baseline, 43.3% at 1 yr, and 29.9% at 2 yrs. UA levels, plasma NE, BMI and BP levels at entry were greater in the non-WL group compared to the WL group, whereas HOMA-IR at entry were similar between the WL and non-WL groups. BMI, BP...
Inhibition of H3K9 histone methyltransferase G9a attenuates renal fibrosis and retains klotho expression
Authors: Taisuke Irifuku, Shigehiro Doi, Kensuke Sasaki, Toshiki Doi, Ayumu Nakashima, Toshinori Ueno, Kyoko Yamada, Koji Arihiro, Nobuoki Kohno, Takao Masaki
Journal: Kidney International (2015)
Efficacy of lower dose of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer resistant to platinum-based therapy.
Authors: V. Michalaki, S. Gennatas, C. G. Gennatas
Journal: Journal of Clinical Oncology (2010)

5116 Background: Topotecan at a dose of 1.5 mg/m2 on days 1 to 5 of a 21-day cycle is indicated in the treatment of advanced-stage ovarian cancers refractory to prior platinum-based regimen. However, many pretreated patients may be predisposed to hematologic adverse events. The aim of this phase II study was to assess the safety and efficacy of a weekly administration of a lower dose of topotecan in patients with recurrent ovarian or peritoneal cancer, having relapsed after platinum/taxane-based first-line chemotherapy. Methods: Patients with advanced ovarian and peritoneal cancer with progression of disease ≤8 months after first-line chemotherapy were enrolled to receive topotecan (2.5 mg/m2) on days 1, 8 and 15 (q 28 d). The primary endpoints were dose density, response rate, and overall tolerance. Results: Thirty-two patients were enrolled in the study and all were evaluable. Twenty-four patients (75%) had measurable disease at baseline and 8 (25%) had elevated CA125 only. In order to avoid dose delays and need for GCSF administration, the dose of topotecan was lowered to 2.5 mg/m2. Of the 32 enrolled patients (median age, 61 years; range, 36 to 78 years), 30 patients had ovarian cancer, and 2 patients had peritoneal cancer. A median of 9 topotecan cycles was administered. Of 32 response-evaluable patients, 6 (19%) had a partial response, 14 (43%) had stable disease, and 12 (38%) had progressive disease. Median duration of response was 4.8 months. Lower dose weekly topotecan was well tolerated: 6 (18 %) patients had grades 2-3 neutropenia, and 8 (25%) had grades 2-3 fatigue. No grade 4 thrombocytopenia or anemia was reported. No patient was admitted with neutropenic fever. Approximately 80% of the patients received the complete schedule of treatment, dose interruptions/delays being mainly due to moderate thrombocytopenia or neutropenia. Conclusions: Lower dose of weekly topotecan was well tolerated in patients with platinum-resistant ovarian or peritoneal cancer at first relapse, with a favourable hematologic profile. Moreover, antitumor activity was similar to that reported for the standard dose of weekly regimen. No significant financial relationships to disclose.
Accuracy and comprehensiveness of pathology reportage after lung cancer resection
Authors: A. Farooq, R. U. Osarogiagbon, J. W. Allen, T. F. O'Brien, D. Spencer, A. Berry
Journal: Journal of Clinical Oncology (2009)

6523 Background: Decisions about prognosis, adjuvant chemo/radiation therapy and clinical trial eligibility require careful examination of the surgical resection specimen. In January 2004, the College of American Pathologists (CAP) and the American College of Surgeons Committee on Cancer mandated reportage of specific items after resection of lung cancer. The extent of compliance is unknown. Methods: We examined final pathology reports for all lung cancer resections in the Memphis Metropolitan Area from January 2004 to December 2007. End-points were the percentage of reports with each CAP item and the 6 most vital determinants of post-operative management and accuracy of TNM staging. Chi-square test was used for year to year comparisons. Results: Table 1 shows frequency of reportage of CAP items. Of those with reported pT stage, it was accurate in 242 of 263 (92.02%) identified as T1; 193 of 208 (92.79%) T2; 21 of 24 (87.5%) T3; 11 of 11 (100%) T4. The most common T-staging error, understaging of satellite nodules (T4), occurred in 12 of 21 (57%) mis-staged as T1, 11 of 15 (73%) T2, 3 of 3 (100%) T3. Overall, 62.6% of reports accurately identified pT-stage. Of those with reported pN-stage, 351 of 352 (99.7%) accurately identified N0; 69 of 81 (85.2%) accurately identified N1, 12 of 81 (14.81%) N1 designations were actually N2; 27 of 27 (100%) N2 designations were accurate; 31 of 34 (91.2%) identified as Nx (no lymph nodes in the specimen) were accurate, 3 (8.8%) were truly N0. Overall, 64.08% of reports accurately identified pN-stage. 4 of 503 identified as pMx (0.8%) had pM1. There was no change in proportion of incomplete and/or inaccurate pathology reports over the 4 years of analysis. Conclusions: Pathology evaluation of lung cancer resection specimens is frequently incomplete or inaccurate, potentially impairing clinical decision-making. Satellite nodules are often understaged. Simple corrective interventions such as enforcement of mandatory institutional utilization of the CAP checklist and AJCC staging manual need to be investigated. [Table: see text] [Table: see text]