tbuckley/cabot-search huggingface dataset:
Abstract 15955: Widely Varying Prevalence of Diastolic Dysfunction by Different Classification Criteria: The Cardia Study
Authors: Laura Rasmussen-Torvik, Laura Colangelo, Joao Lima, Daivd Jacobs, Carlos Rodrigez, Donald Lloyd-Jones, Sanjiv Shah
Journal: Circulation (2014)

Background: Diastolic dysfunction is an important target for investigations attempting to understand heart failure with preserved ejection fraction. The many existing classification criteria for diastolic dysfunction could identify widely different case mixes in large cohort studies with research echocardiographic data. We compared prevalence of diastolic dysfunction at the Y25 exam in CARDIA using definitions of diastolic dysfunction proposed by the American Society of Echocardiography (ASE), Rochester County Epidemiology Project (Redfield), and the VALIDD trial. Methods: 3474 CARDIA participants had echocardiographic data at Y25. Echocardiographic exams were performed at the CARDIA Y25 exam. At each center, trained echo techs obtained images by a standardized protocol and scans were read centrally. Standard 2D and M-mode assessments were obtained. Published binary definitions of diastolic dysfunction were applied; pulmonary venous flow and mitral inflow at peak Valsalva maneuver measures were not available in CARDIA, so the (modified) Redfield definition of diastolic dysfunction was based on two of the four variables included in the definition. Logistic regression was used to determine demographic predictors of diastolic dysfunction. Results: The mean age in the sample was 50.2 years, mean BMI was 30.2 kg/m2, 46.7% of the sample was African American and 53.3% was white. The prevalence of diastolic dysfunction according to different definitions was as follows: 1.6 % according to the ASE definition, 24.3% according to the VALIDD definition, and 32.0% according to the (modified) Redfield definition. Using the ASE definition, 38.9% of individuals were unclassifiable for diastolic dysfunction. After adjustment for age, sex, and BMI, African Americans had 7.0 (95% C.I.: 3.4-14.4) times the odds of having diastolic dysfunction compared to whites according to the ASE definition. The comparable OR was 1.9 (95% C.I.: 1.6-2.2) for the Redfield Definition and 1.9 (95% C.I.: 1.6-2.2) for the VALIDD definition. Discussion: Existing definitions for diastolic dysfunction are difficult to implement in cohort studies and provide widely varying estimates for the prevalence of diastolic dysfunction as well as for predictors of diastolic dysfunction.
Docetaxel re-treatment for metastatic hormone refractory prostate cancer
Authors: J. Ansari, S. A. Hussain, A. Zarkar, J. Bliss, J. S. Tanguay, J. Glaholm
Journal: Journal of Clinical Oncology (2008)

16066 Background: Recent clinical trials have established three-weekly docetaxel chemotherapy along with prednisolone (3wD+P) as standard of care for patients with metastatic hormone refractory prostate cancer (MHRPC). A significant proportion of patients receiving first- line 3wD chemotherapy (CT) will be eligible for second-line CT on biochemical disease progression (BDP), however, there are no other licensed CT options. The efficacy and toxicity with 3wD CT re-treatment has not been previously reported in patients who respond to docetaxel and then progress after a period of biochemical remission. Methods: A total of43 patients with MHRPC were treated at our institution with 3wD 75 mg/m2 + P 10 mg daily. The median patient age was 73 years and the median PSA at CT initiation was 182 (range 19.9->1500) ng/ml. Of 43 patients, 10 were re-treated with 3wD+P (2nd line CT) on BDP. A further 3 out of these 10 patients received 2nd re-treatment with 3wD+P (3rd line CT) on BDP. We assessed PSA response, toxicity, overall survival for first-line docetaxel CT and subsequent re-treatment. Results: Of 43 patients, 37% had PSA decline of >50% and 14% had PSA declines of 30–50% of pre-treatment levels; 19% had stable disease and 23% had progressive disease. On 1st re-treatment, 7 out of 10 patients who had responded to first-line CT responded again with a PSA reduction >50%. 3 out of these 7 patients received 2nd re-treatment, with all 3 patients achieving PSA reduction >50% of pre-treatment levels. The median treatment-free interval prior to 1st and 2nd re-treatments was 24 and 26 weeks, respectively. The median overall survival was 16 (range 1–35) months. There was a significant rise in the incidence of grade 3/4 neutropenia with re-treatment, though no treatment-related deaths. Conclusions: To our knowledge, this is the first evidence supporting 3wD re-treatment, demonstrating that MHRPC patients responding to 1st line docetaxel CT maintain their intrinsic sensitivity to subsequent re-treatment. Analogous to intermittent androgen ablation, intermittent administration of CT is an attractive proposition which may offer patients improved quality of life during treatment-free periods. Based on these results, the role of intermittent 3wD CT needs to be prospectively evaluated in clinical trials. No significant financial relationships to disclose.
Integrated genomic analysis of lung adenocarcinomas identifies loss of the MAPK phosphatase gene <i>DUSP4</i> in most <i>EGFR</i> mutant tumors
Authors: S. R. Broderick, D. Chitale, N. Motoi, Y. Gong, W. Pao, E. Venkatraman, V. Rusch, C. Brennan, W. Gerald, M. Ladanyi
Journal: Journal of Clinical Oncology (2007)

7686 Background: Genomic analyses of lung adenocarcinoma have yielded striking advances that are already impacting on clinical management. Further advances in understanding the biological heterogeneity of this disease will require integration of multiple types of genomic data. To this end, we have assembled a large integrated genomics dataset of lung adenocarcinomas. Here, we highlight one of the novel findings emerging from its initial analysis. Methods: 173 primary lung adenocarcinomas were included in this analysis. Profiling of genomic gains and losses was done by array comparative genomic hybridization (aCGH) on Agilent 44K arrays. Expression profiling was based on Affymetrix U133A arrays. The dataset was annotated for EGFR mutations (exon 19 deletion and L858R) by sensitive PCR-based assays and for KRAS mutations by sequencing. Results: By unsupervised analysis of the aCGH data, the 173 tumors clustered robustly into two or three patterns of co-occurring gains and losses. One aCGH cluster was strongly associated with EGFR mutation (p&lt;10 −4 ) and was characterized by 7p gains (in the EGFR region) and 8p losses. Remarkably, by expression profiling the most consistently underexpressed gene (p&lt;10 −9 ) in EGFR mutant cases compared to EGFR wild type cases was a MAPK phosphatase gene at 8p12, DUSP4 (MKP-2). The DUSP4 region showed genomic loss in 27/35 EGFR mutant cases vs 47/138 non-mutated cases (p&lt;10 −4 ). A limited screen (n=11) has so far revealed no DUSP4 mutations. Western blotting shows low DUSP4 in most EGFR mutant lines, compared to KRAS mutant lines. Conclusions: EGFR mutations in lung adenocarcinomas are strongly associated with genomic loss and low expression of DUSP4. DUSPs are known to be transcriptionally upregulated by MAPK signaling as a negative feedback mechanism and DUSP family members are emerging as putative tumor suppressors in other cancers. We hypothesize that DUSP4 loss cooperates with EGFR mutation to allow full oncogenic activation of the MAPK pathway. Functional studies of DUSP4 in lung adenocarcinoma cell lines are in progress. Our data highlight the value of large, integrated, highly annotated genomic datasets in generating novel insights and hypotheses. No significant financial relationships to disclose.
Ablating MUC1+ tumor and cancer stem cells by targeting the MUC1 oncoprotein with configurational-specific monoclonal antibodies and peptides.
Authors: D. B. Rubinstein, E. Pichinuk, N. Smorodinsky, D. H. Wreschner
Journal: Journal of Clinical Oncology (2010)

e13088 Background: MUC1, a glycoprotein overexpressed by breast, intestinal, pancreatic, and gastric adenocarcinomas is a heterodimer with an extracellular α chain that is noncovalently bound to a membrane-bound β subunit. The α-chain's “on-again-off-again” interaction with the β-chain results in intracellular signaling. The MUC1 oncoprotein is an outstanding candidate for targeted therapy. Almost all anti-MUC1 Abs reported recognize the highly immunogenic α subunit. Because the α subunit is shed into the peripheral circulation it sequesters anti-α chain Abs, precluding their reaching MUC1+cancer cells, and clinical trials to date have been ineffective. Methods: We identified the MUC1 SEA module that comprises the α/β junction, which, being attached at all times to the cell surface represents a therapeutically exploitable target, and generated a series of anti-MUC1 junction IgGγ1 monoclonal Abs (mAbs) denominated DMB mAbs. Results: The novel mAbs bound strongly to MUC1-expressing cancer cells including T47D and ZR-75, and on FACS strongly bound the self-reproducing MCF-7 side population representing breast cancer stem cells. The mAbs were nonreactive as probes in Western blots of the MUC1 protein on denaturing SDS gels, suggesting that the epitopes recognized are configurational. Analysis of mAbs binding to a series of generated mutant MUC1 isotypes suggested that the N-terminal portion of the MUC1 protein binds to the SEA module, thereby forming the precise epitopes recognized by our mAbs. We proceeded to develop small peptides derived from the MUC1 N-terminus that selectively bind the MUC1 SEA epitope. Conclusions: (i) Small molecules and mAbs can target biologically significant epitopes of the cell-bound MUC1 α/β junction. (ii) targeting specific conformationaly determined sites within the α/β junction overcomes limitations of Abs which target circulating moieties of the MUC1 molecule. (iii) Because of their selective binding, the epitope-specific anti-MUC1 junction mAbs and peptides described here may prove highly effective in selectively targeting not only MUC1+ tumors but also the repopulating cancer stem cells that allow tumor regrowth. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biomodifying
Capsaicin induces G1/S cell cycle arrest leading to apoptosis of multiple myeloma cells through suppression of STAT3 activation and STAT3-regulated gene products
Authors: M. Bhutani, A. K. Pathak, G. Sethi, B. B. Aggarwal
Journal: Journal of Clinical Oncology (2006)

20039 Background: Agents that can block activated STAT3, a central player for proliferation, cell survival and chemoresistance, have a potential as therapeutic agents for the treatment of Multiple Myeloma (MM). Capsaicin, a spicy component of hot pepper, is a homovanillic acid derivative that preferentially induces certain cancer cells to undergo apoptosis. We have previously shown that Capsaicin blocked activation of NF-kappa B in human myeloid ML-1a cells. In this study we evaluated the effect of Capsaicin on STAT3 in MM cells. Methods: We used U266, a well-characterized MM cell line, which constitutively expresses activated STAT3. MM cells treated with Capsaicin were subjected to western blot analysis with specific antibodies to STAT3, tyrosyl phosphorylated STAT3 and STAT5. The effect of Capsaicin on nuclear-cytoplasmic compartment of STAT3 was studied by immunocytochemistry. The antiproliferative effect of Capsaicin was determined by the MTT assay and the effect on the cell cycle was determined by flowcytometry. Apoptosis of cells was measured using the Live and Dead assay. To determine the downstream targets like antiapoptotic proteins (Bcl-xL, Bcl-2, and Survivin), and cell cycle-regulators (cyclin D1) immunoblot analysis of Capsaicin treated cells was performed. Results: Capsaicin suppressed the constitutive activation of STAT3 in human MM cells in a dose- and time-dependent manner, prior to cell death. Capsaicin’s effect on STAT3 was specific as STAT5 was unaffected. Capsaicin depleted nuclear pool of STAT3 in U266 cells. Abrogation of constitutive STAT3 phosphorylation in MM cells induced G1 cell cycle arrest. The antiapoptotic proteins BCl-xl, suvivin, cyclin D1, and Bcl-2, which are encoded in target genes of STAT3, were down regulated by Capsaicin, followed by induction of apoptosis through activation of caspase-3. We further demonstrated that low dose combined Capsaicin and thalidomide/ bortezomib treatment triggered synergistic cytotoxicity. Conclusions: These findings suggest that the antitumor activity of Capsaicin is at least partially due to inhibition of STAT3 pathway and provide a basis for potential application of Capsaicin for treatment of relapsed and refractory MM. No significant financial relationships to disclose.
High rate of TRG1–2 and prolonged RFS with OXA/TOM and FU/LFA during preoperative pelvic RT in patients with poor prognosis locally advanced rectal cancer (LARC)
Authors: A. Avallone, P. Delrio, C. Guida, F. Tatangelo, A. Petrillo, S. Lastoria, V. Parisi, G. Comella, A. Budillon, P. Comella
Journal: Journal of Clinical Oncology (2007)

14500 Background: We have previously reported that 3 cycles of Oxaliplatin (OXA), Raltitrexed (TOM) and 5-Fluorouracile (FU) + levo-folinic acid (LFA) during pelvic RT had an acceptable toxicity and produced a complete (TRG1, 42%) or subtotal (TRG2, 29%) pathologic tumor regression in 71% of 31 pts with poor prognosis LARC (Avallone et al, Br J Cancer 2006). Here we report an expanded experience on such treatment. Methods: We enrolled 62 eligible pts (M, 33; F, 29), with median age of 58 (27–79) yrs, and adenocarcinoma of the extraperitoneal rectum, with at least one of the following characteristics: cT4 (N pts), cN+ (N), cT3N0 with tumor location = 5 cm from the anal verge and/or CRM +ve (assessed by MRI) (N). Pts received 3 biweekly courses of OXA 100 mg/sqm + TOM 2.5 mg/sqm on day 1, and LFA 250 mg/sqm + FU 900 mg/sqm (31 pts) or 800 mg/sqm (31 pts) on day 2, and concomitant pelvic RT (1.8 Gy/day, total dose 45 Gy). TME was planned 8 weeks after the end of treatment. Pathologic response was evaluated by tumor regression grading (TRG) according to Mandard’s modified classification. Pts with cT4, pN+ and pCRM +ve received also 4 months of weekly FU/FA. Results: All pts received full dose of RT, and 98% of the planned CT cycles. Neutropenia was the most common grade = 3 toxicity (40%), while grade 3 diarrhea was seen in 19% of pts with FU 900 mg/sqm, and in only 6% of pts with FU 800 mg/sqm. All but 2 pts had a TME with R0 resection, and no treatment-related or perioperative death occurred. Median number of sampled lymph nodes was 36 (range, 10–80). 28 (45%) pts obtained a TRG1, and 17 (27%) pts a TRG2. Activity of the treatment was similar in all risk groups, regardless of FU dosage. 1 pt suffered a local recurrence (after 9 months), and 3 pts had distant metastases (after 22, 33, and 47 months). After a median follow-up of 34 (range 6–54) months, all pts are alive, and the estimated 34-month RFS was 95%. All pts achieving a TRG1, and all but one with TRG2 (pCRM +ve), were recurrence-free. Conclusions: These data confirm the feasibility and activity of the whole treatment. A slight reduction of FU dosage appeared to improve the safety of this combination. Currently, we are now evaluating the addition of bevacizumab 5 mg/kg every 2 weeks before and during this concurrent treatment. No significant financial relationships to disclose.
Retinal nerve fibre layer and visual function loss in glaucoma: the tipping point
Authors: Gadi Wollstein, Larry Kagemann, Richard A. Bilonick, Hiroshi Ishikawa, Lindsey S. Folio, Michelle L. Gabriele, Allison K. Ungar, Jay S. Duker, James G. Fujimoto, Joel S. Schuman
Journal: BMJ (2011)

Aims To determine the retinal nerve fibre layer (RNFL) thickness at which visual field (VF) damage becomes detectable and associated with structural loss. Methods In a prospective cross-sectional study, 72 healthy and 40 glaucoma subjects (one eye per subject) recruited from an academic institution had VF examinations and spectral domain optical coherence tomography (SD-OCT) optic disc cube scans (Humphrey field analyser and Cirrus HD-OCT, respectively). Comparison of global mean and sectoral RNFL thicknesses with VF threshold values showed a plateau of threshold values at high RNFL thicknesses and a sharp decrease at lower RNFL thicknesses. A ‘broken stick’ statistical model was fitted to global and sectoral data to estimate the RNFL thickness ‘tipping point’ where the VF threshold values become associated with the structural measurements. The slope for the association between structure and function was computed for data above and below the tipping point. Results The mean RNFL thickness threshold for VF loss was 75.3 mm (95% CI: 68.9 to 81.8), reflecting a 17.3% RNFL thickness loss from age-matched normative value. Above the tipping point, the slope for RNFL thickness and threshold value was 0.03 dB/mm (CI: � 0.02 to 0.08) and below the tipping point, it was 0.28 dB/mm (CI: 0.18 to 0.38); the difference between the slopes was statistically significant (p<0.001). A similar pattern was observed for quadrant and clock-hour analysis. Conclusions Substantial structural loss (w17%) appears to be necessary for functional loss to be detectable using the current testing methods.
Prediction of colorectal cancer relapse and survival via tissue RNA levels of matrix metalloproteinase-9.
Authors: Z S Zeng, Y Huang, A M Cohen, J G Guillem
Journal: Journal of Clinical Oncology (1996)

PURPOSE In this study, we investigated the association between matrix metalloproteinase (MMP)-9 RNA expression in primary colorectal cancer (CRC) and standard clinicopathologic variables and determined whether levels of MMP-9 RNA predict relapse and survival. PATIENTS AND METHODS Tumor and paired normal mucosa specimens from 71 primary CRC patients following resections were assessed. RNA levels were determined via Northern blot hybridization and quantitated with laser densitometry. Results were expressed as tumor/normal mucosa (T/N) fold-increase calculated after normalizing for RNA loading using 28S expression. Statistical analysis was performed using the SAS statistical package procedure. Kaplan-Meier survival curves were compared with the two-sided log-rank test. RESULTS The mean T/N MMP-9 RNA fold-increase was 9.4 +/- 1.0 (mean +/- SE) (P &lt; .001). Overexpression of MMP-9 RNA correlated significantly with status of synchronous distant metastases (M stage) (P = .004) and Dukes' stage (P = .008). A T/N fold-increase of 5.0 was used to discriminate between high (&gt; 5.0) and low (&lt; or = 5.0) T/N MMP-9 expression. High T/N MMP-9 RNA expression was associated with a significantly shorter disease-free (P = .0001) and overall (P = .0002) survival duration. In univariate and multivariate analyses, T/N MMP-9 RNA level was found to be an independent prognostic factor for disease-free survival. CONCLUSION This report provides the first evidence that increased MMP-9 RNA production in primary human CRC may be a powerful, independent predictor of recurrence and outcome.
Phase I and pharmacokinetic study of the multidrug resistance modulator dexverapamil with EPOCH chemotherapy.
Authors: W H Wilson, C Jamis-Dow, G Bryant, F M Balis, R W Klecker, S E Bates, B A Chabner, S M Steinberg, D R Kohler, R E Wittes
Journal: Journal of Clinical Oncology (1995)

PURPOSE Dexverapamil is a competitive inhibitor of the P-glycoprotein (Pgp) efflux pump, a potent mechanism of multidrug resistance (mdr-1) in vitro. We performed a phase I study to determine the maximum-tolerated dose (MTD) and pharmacokinetics of dexverapamil with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) chemotherapy. PATIENTS AND METHODS Eligible patients had relapsed or refractory lymphoma or sarcoma. Patients initially received EPOCH alone, and those with stable or progressive disease were crossed-over to received dexverapamil on subsequent cycles of EPOCH. Dexverapamil was administered orally for 6 days and escalated over eight dose levels ranging from 240 to 1,200 mg/m2/d. Pharmacokinetics of dexverapamil and its active metabolite, nor-dexverapamil, were obtained in most patients. In seven patients, pharmacokinetics of doxorubicin, doxorubicinol, and etoposide were determined on paired cycles of EPOCH with or without dexverapamil. RESULTS Sixty-five patients received 130 cycles of dexverapamil/EPOCH chemotherapy. The MTD of dexverapamil was 150 mg/m2 every 4 hours (900 mg/m2/d), and hypotension was the principal dose-limiting toxicity. The dexverapamil area under the curve (AUC) increased proportionally with dexverapamil dose, but significant interpatient variation occurred. At the MTD, the median plasma average concentrations of dexverapamil and nor-dexverapamil were 1.2 and 1.4 mumol/L, respectively. Dexverapamil did not affect the steady-state concentration (Css) of etoposide, but increased the Css of doxorubicin and doxorubicinol nearly twofold. The absolute neutrophil and platelet nadirs were significantly lower on the dexverapamil cycles compared with cycles of EPOCH alone, but other chemotherapy-related toxicities did not change. CONCLUSION The phase II recommended dose of dexverapamil with EPOCH is 150 mg/m2 every 4 hours. This dose was well tolerated on an outpatient basis and achieved plasma concentrations of dexverapamil and nor-dexverapamil within the effective range for Pgp inhibition in vitro. Although dexverapamil increased the hematopoietic toxicity of EPOCH, it was mild, readily reversible, and offset by EPOCH dose reductions. Dexverapamil should be considered for further study.
Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin lymphoma (NHL)
Authors: A. Reiter, A. Meinhardt, B. Burkhardt, M. Zimmermann, A. Borkhardt, U. Kontny, G. Mann, M. Schrappe
Journal: Journal of Clinical Oncology (2009)

10000 Background: Pediatric mature B-cell NHL differ from aggressive B-NHL of adults in terms of biology and treatment outcome. In contrast to adults, rituximab (Rx) is not established in the treatment of pediatric B-NHL has not be determined yet. Even the activity of Rx in pediatric B-NHL is not determined. We conducted a phase II window study to examine the activity of Rx in newly diagnosed pediatric B-NHL. Methods: Eligibility: age &lt; 19 y, CD20 + B-NHL, ≥ 1 measurable lesion/s, informed consent. Exclusion: Lansky performance scale 5, pre-treatment, impaired renal-, heart-, liver-function, hepatitis B, pre-existing disease, pregnancy. Treatment: Rx 375 mg/m 2 IV at day 1; concomitant therapy: Rasburicase, steroids only for anaphylaxis, intrathecal (IT) triple drug at days 1, 3 for CNS+ pts only. Begin of chemotherapy at day 5. Response evaluation: product of 2 perpendicular diameters of 1 - 3 index lesions/% blasts in BM/PB within 24 h prior to Rx and at day 5: responder (RP): at least 1 lesion with at least objective effect (decrease of ≥25%) and no progress (increase of ≥25 %) at other sites. Study plan: Simon 2-stage phase II with α and β = 5%. Response rate (RR) for poor activity was set to 45%, for good activity 65%. 33 pts entered the first stage, final evaluation after 79 pts. Results: One hundred thirty-six pts were enrolled from 04/04–08/08. NTC °3/4 toxicities: general condition 16%, fatigue 13%, anaphylaxis (chill/fever/bronchospasm) 6 (1/2/4)%, infection 3%, S-GOT/GPT 10%, acute tumor lysis (ATL) 7%, capillary leakage (0), toxic death (0). Forty-nine pts were not evaluable for response: Withdrawal (anaphylaxis 8, ATL 2, suspected progression, not verified 4, other 2), IT therapy in CNS- pts (8), corticosteroids (3), technical inadequacy of response evaluation (21), no index lesion (1). Of the 87 evaluable pts 37 were RPs (42.5%, 95%-CI 32% - 54%). RR by histology: BL/B-ALL 29/68, DLBCL 6/14, juvenile follicular lymphoma 1/2, PMBCL 1/1, B-NHL nfs 0/2. Fifty pts were non-RPs. Conclusions: Although the RR was lower than requested Rx as single agent is active in pediatric B-NHL. No significant financial relationships to disclose.