tbuckley/cabot-search huggingface dataset:
Lipid and coagulation profile in postmenopausal women with early breast cancer at low risk treated with exemestane: A randomized, placebo-controlled study
Authors: L. E. Krag, J. Geisler, P. E. Lonning, L. Ottestad, T. Risberg, A. I. Hagen, E. A. Lien, A. Polli, J. Paolini, G. Massimini
Journal: Journal of Clinical Oncology (2004)

650 Background: Estrogens (Es) favorably modify the lipid profile. Aromatase inhibitors reduce Es; LDL and triglycerides (tri) increase have been observed (Elisaf, EJC 2001). We report the effect of exemestane (E, Aromasin), a steroidal aromatase inactivator, on lipid profile and coagulation in postmenopausal early breast cancer (EBC) patients (pts). Methods: We conducted a randomized, double blind study on the effect of E on bone metabolism, endocrinological and metabolic parameters in postmenopausal pT1N0 or T2N0 (with no other risk factors) or ductal carcinoma in situ (DCIS) pts. ER and/or PgR+ve or unknown pts with bone mineral density (BMD) within 2 SD of the mean for 65-years (yrs) women were randomized to E 25 mg day or placebo (P) p.o. for 2 yrs, with a 1-yr follow-up. Primary objective was non-inferiority on BMD. Planned sample size was 128 BMD-evaluable pts. Cholesterol (Chol), HDL-cholesterol (HDL-c), tri, Apo-AI, Lipoprotein A (Lipo-AI), Apo B, PT, APTT, fibrinogen (Fib) and homocysteine (hoc) were evaluated at baseline (BS), 6, 12, and 24 months (mos). Results: 147 pts have been enrolled, 73 E and 74 P. Median age: 61 yrs (E) and 60 yrs (P). Median time from menopause: 9.7 yrs E and 8.0 yrs P. ER and/or PgR: +ve 130 pts, unknown 17 (15 with DCIS). E was well tolerated, 70% of pts had drug-related events on E and 73% on P. Nine pts withdrew on E and 3 on P for adverse events (1 E for DVT and 2 P for increased Fib or apoplexia). No PT changes from BS were observed on both arms. At 24 mos median Fib was reduced by 1.2% on E and 4.8% on P, and median APTT by 3% on both. Lipid profile evolution is described in the Table. Out of 64 E pts, 4 developed Gr. 2 Chol, and 1 Gr. 1 Tri elevation. Out of 62 P pts, 7 developed Gr. 2 and 1 Gr. 1 Chol, 3 Gr. 1 Tri elevations. Conclusions: After 2 yrs of E, lipid profile and homocysteine levels are similar in E and P pts, except for a modest reduction in HDL-c on E. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Italia S.p.A. Pfizer Co. Pfizer Co.
Evolution at the tip and base of the X chromosome in an African population of Drosophila melanogaster.
Authors: D J Begun, C F Aquadro
Journal: Molecular Biology and Evolution (1995)

Hitchhiking effects of advantageous mutations have been invoked to explain reduced polymorphism in regions of low crossing-over in Drosophila. Besides reducing DNA heterozygosity, hitchhiking effects should produce strong linkage disequilibrium and a frequency spectrum skewed toward an excess of rare polymorphisms (compared to the neutral expectation). We measured DNA polymorphism in a Zimbabwe population of D. melanogaster at three loci, yellow, achaete, and suppressor of forked, located in regions of reduced crossing-over. Similar to previously published surveys of these genomic regions in other populations, we observed low levels of nucleotide variability. However, the frequency spectrum was compatible with a neutral model, and there was abundant evidence for recombination in the history of the yellow and ac genes. Thus, some aspects of the data cannot be accounted for by a simple hitchhiking model. An alternative hypothesis, background selection, might be compatible with the observed patterns of linkage disequilibrium and the frequency spectrum. However, this model cannot account for the observed reduction in nucleotide heterozygosity. Thus, there is currently no satisfactory theoretical model for the data from the tip and base of the X chromosome in D. melanogaster.
Treatment of Relapsed Acute Promyelocytic Leukemia by Arsenic-Based Strategies without Hematopoietic Stem Cell Transplantation in Hong Kong: A Seven-Year Experience.
Authors: Wing Y. Au, James C. Chim, Albert K. Lie, Cyrus R. Kumana, Anskar Y. Leung, Eric W. Tse, Shing Y. Ma, Raymond H. Liang, Yok L. Kwong
Journal: Blood (2004)
Optimization of patient selection for EGFR-TKIs in advanced non-small cell lung cancer by combined analysis of MET, EGFR, KRAS, and PIK3CA mutations.
Authors: V. Ludovini, F. Bianconi, L. Pistola, R. Chiari, F. R. Tofanetti, A. Siggillino, E. Baldelli, R. Colella, M. G. Mameli, L. Crinò
Journal: Journal of Clinical Oncology (2010)

7562 Background: Specific EGFR tyrosine Kinase inhibitors (TKIs) have been developed and used for the treatment of advanced NSCLC. Somatic activating mutations of EGFR gene and some clinical and pathological features have been associated with tumor response and favourable clinical outcome with these agents. However, tumor that initially respond to EGFR-TKIs almost inevitably become resistant later. We present a comprehensive analysis of MET, EGFR, KRAS and PIK3CA mutations in advanced NSCLC patients treated with TKIs, with the aim of clarifying the relative contribution of these molecular alterations to resistance. Methods: Genomic DNA was isolated from paraffin-embedded tumor specimens, amplified for MET (exons 14, 15), EGFR (exons 18, 19, 20 and 21), PIK3CA (exons 9, 20) KRAS (exons 2, 3) by nested PCR and sequenced in both sense and antisense directions. Among all the mutations evaluated, only TKIs no-sensitive mutations were used for time to progression (TTP) and overall survival (OS) analysis. Results: Median age was 60.2 yrs (range 25.6-84), M/F: 91/75; adeno/bac/other: 102/17/47; never/former/current/unknown smokers:61/47/46/12. One hundred sixty-six patients (pts) have been treated with TKIs. MET, sensitive EGFR (exons 19 and 21), no-sensitive EGFR (exons 18 and 20), KRAS and PIK3CA mutations were detected in 3.8%, 19.4%, 3.0%, 6.8% and in 4.1% of pts, respectively. Patients with TKIs no-sensitive mutations showed a progression (96%, p = 0.0018). Median TTP of pts with TKIs no-sensitive mutations was 2.23 months vs 6.63 months (p < 0.0001) of other group. At univariate analysis of OS TKIs no-sensitive mutations were associated with worse prognosis (16.1 months vs 30.2 months, p = 0.02). Cox's multivariate analysis including histology and stage showed that TKIs no-sensitive mutations were independent factors to predict poor OS (p = 0.02). Conclusions: When TKIs no-sensitive MET, KRAS, PIK3CA and EGFR mutations are concomitant, up to 96% of NSCLC patients unlikely to respond to anti-EGFR therapies, can be identified. Comprehensive molecular dissection of EGFR signalling pathways should be considered to select advanced NSCLC patients for TKIs therapies. No significant financial relationships to disclose.
Patients’ conceptions of drug information given by the rheumatology nurse
Authors: Ingrid Larsson, Susann Arvidsson, Stefan Bergman, Barbro Arvidsson
Journal: Annals of the Rheumatic Diseases (2009)

Background: Pain, stiffness and functional restriction of the joints are the main problems for patients with inflammatory rheumatic conditions. The majority of patients with rheumatic diseases have ...
Gene expression signature predicts chemoresponse of microdissected papillary serous ovarian tumors
Authors: L. Ozbun, T. Bonome, M. E. Johnson, M. Radonovich, C. Pise-Masison, J. Brady, S. Mok, M. E. Birrer
Journal: Journal of Clinical Oncology (2006)

5064 Background: The purpose of this study was to identify a predictive gene signature for chemoresponse in patients with advanced stage papillary serous ovarian cancer. Methods: Expression profiling was performed on 50 chemonaive, microdissected advanced stage papillary serous ovarian cancers using Affymetrix Human Genome U133 Plus 2.0 microarrays. Chemoresistance was defined as disease progression while the patients remained on primary chemotherapy. Nine normal human ovarian surface epithelial (HOSE) brushings were also assessed to quantify normal gene expression levels. Validation was performed by quantitative real time PCR using the HOSE isolates and microdissected ovarian tumor samples. Results: A supervised learning algorithm applied to genes differentially expressed between chemosensitive/resistance tumors (p &lt; 0.001) using leave-one-out cross-validation (LOOCV), identified over 2000 genes associated with tumor chemosensitivity. The chemoresponsive gene list was further refined to 576 genes by including only genes used for all LOOCV iterations. An independent gene list was generated comparing expression profiles of chemoresistant tumors to HOSE. The two lists were compared to identify common genes, generating final classifier list of 75 genes that included genes involved in apoptosis, RNA processing, protein ubiquitination, transcription regulation, and other novel genes. We hypothesized genes identified in both data sets would be predictive and biologically relevant. Of these 75 genes, 20 were validated by real-time PCR. Validated genes were ranked by a univariate t-stat value to further resolve the predictor. 4 multivariate predictor algorithms demonstrated the 10 top ranked validated genes maximixed prediction accuracy (compound covariate, 91%; diagonal linear discriminant analysis, 91%; 3-nearest neighbor, 86%; nearest centroid, 95%). The predictive value of these genes will be evaluated on an independent sample set. Conclusions: Gene expression profiling can distinguish between chemosensitive and chemoresistant ovarian cancers. This signature can predict response to therapy and has identified novel biologically and clinically relevant targets. No significant financial relationships to disclose.
Safety of different regimens of the novel integrin inhibitor cilengitide combined with cetuximab and platinum-based chemotherapies.
Authors: J. F. Vansteenkiste, T. Brümmendorf, W. Schuette, J. Guigay, C. F. Waller, R. Mesia, P. Germonpre, S. Bohnet, J. B. Vermorken
Journal: Journal of Clinical Oncology (2010)

e18067 Background: Cilengitide is an investigational selective αvβ3/5 integrin inhibitor in clinical development for advanced non-small cell lung cancer (NSCLC) and squamous cell head and neck cancer (SCCHN). The CERTO (NSCLC) and ADVANTAGE (SCCHN) trials assess the safety and activity of cilengitide in combination with platinum-based chemotherapy and cetuximab. Methods: CERTO and ADVANTAGE are randomized, open-label, multicenter controlled trials with a safety run-in/dose escalation phase I (completed) and a randomized phase II part (ongoing). Both safety run-in phases examine cilengitide 1,000 or 2,000 mg twice weekly (ADVANTAGE also examined 500 mg) combined with cetuximab (400 mg/m2 first dose; 250 mg/m2/week thereafter) and platinum-based chemotherapy every 3 weeks (cisplatin 80 mg/m2/vinorelbine 25 mg/m2 or cisplatin 75 mg/m2/gemcitabine 1,000 mg/m2 for CERTO; cisplatin 100 mg/m2 and 5-fluorouracil 4,000 mg/m2 for ADVANTAGE). The randomised phases (NSCLC, n = 189; and SCCHN, n = 177) have 3 arms, comparing standard therapy alone, or with cilengitide 2,000 mg given either once or twice-weekly. Eligible subjects are ≥ 18 years old with 1 measurable lesion, performance status 0–1 and confirmed advanced SCCHN or NSCLC. The safety run-in determined the maximum tolerated cilengitide dose. Primary endpoint of the ongoing phase II studies is progression-free survival. Results: All subjects from the safety run-ins (n = 12 CERTO; n = 10 ADVANTAGE) experienced at least one treatment related adverse event (AE) but no dose-limiting toxicities (DLT). Three of the total 22 subjects experienced grade 3 AEs related to cilengitide. Discontinuation due to AEs occurred in 2 subjects (haematochezia; hearing loss). The most common (> 1 subject) cilengitide-related AEs were nausea (6 subjects), vomiting (4), fatigue (4), diarrhea (4), asthenia (3), mucosal inflammation (3), epistaxis (3), pyrexia (2), and anorexia (2). Conclusions: Cilengitide combined with standard therapy was well tolerated with no unexpected AEs and no DLTs. Phase II evaluation of cilengitide 2000 mg given once or twice weekly combined with standard therapy is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Serono Merck Serono, seminar presentation “START 2” Merck Serono
Systemic gene therapy with tumor suppressor FUS1-nanoparticles for recurrent/metastatic lung cancer.
Authors: C. Lu, D. J. Stewart, L. Ji, R. Ramesh, G. Jayachandran, J. J. Erasmus, J. Lee, N. S. Templeton, J. D. McMannis, J. A. Roth
Journal: Journal of Clinical Oncology (2010)

7582 Background: The tumor suppressor gene FUS1 is frequently inactivated early in lung cancer (LC) development. FUS1 mediates apoptosis in cancer cells but not normal cells through its interaction with Apaf1. DOTAP:cholesterol nanoparticles encapsulating a FUS1 expression plasmid (DOTAP:chol-FUS1) showed selective uptake by cancer cells and activity in mouse xenograft metastatic LC models. Methods: Patients with recurrent/metastatic LC previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous DOTAP:chol-FUS1. Results: Patients received doses ranging from 0.01-0.09 mg/kg at 3 week intervals. Thirty patients have been treated at 6 dose levels, with all patients evaluable for the primary endpoint of cycle 1 toxicity. 70% had received 2 or more prior chemotherapy regimens. Among 4 patients treated without premedications, all 4 developed grade (G) 2 or higher fevers within 24 hours of treatment. Among the 26 patients premedicated with dexamethasone and diphenhydramine, 7 and 2 subjects developed G1 and G2 fever, respectively. The only dose-limiting toxicities were 2 episodes of transient G3 hypophosphatemia (dose levels 0.06 and 0.09 mg/kg), resulting in a maximum tolerated dose (MTD) of 0.06 mg/kg. Twenty-two patients who received two or more doses were evaluable for response, with 5 achieving stable disease (SD) and 17 progressing. One patient with SD had evidence of a metabolic response on PET imaging. Median survival time for all patients is 9.1 months. Pre and 24 hour posttreatment tumor biopsies were obtained from 6 patients, and quantitative real time reverse transcriptase PCR (RT-PCR) analysis using a plasmid FUS1 sequence-specific probe was performed on these paired-samples blinded to time of biopsy. A high level of plasmid FUS1 expression was detected in 5 of 6 posttreatment samples but not in pretreatment samples and negative controls by RT-PCR. Conclusions: DOTAP:chol-FUS1 can be safely administered intravenously in LC patients with demonstrable gene expression in posttreatment tumor biopsies. The MTD for phase II testing is 0.06 mg/kg every 3 weeks. Based on promising preclinical data, a trial in combination with erlotinib is planned. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Introgen Therapeutics
Spontaneous otoacoustic emissions (SOAE) changes in testicular cancer patients treated with cisplatin: A pilot study of whether the acute ototoxic effect of cisplatin treatment can be detected
Authors: K. Biro, L. Noszek, P. Prekopp, K. Vehovszky, E. Nemeth, K. Nagyivanyi, L. Geczi, I. Gaudi, I. Bodrogi
Journal: Journal of Clinical Oncology (2007)

15581 Background: We studied the acute ototoxic effect of cisplatin in testicular cancer patients with two highly sensitive new methods for detecting high frequency hearing loss: distorsion product otoacoustic emissions (DPOAE), and spontaneous otoacoustic emissions (SOAE). Methods: Checking the acute effect, 32 (63 ears) testicular cancer patients (median age: 33 years, range: 16–59 years) were measured on the first day of their first cycle and after one week of their last cycle of cisplatin treatment. 20 mg/m2 cisplatin was administered for five days, in BEP chemotherapy regimen. The patients got on the average 2.19 cycles (2–3 cycles). We also measured the SOAE of ten healthy control persons (without chemotherapy) matching sex and age distribution of this group. A detailed medical history evaluated audiological risk factors and hearing problems. Tympanometry, DPOAE and SOAE were measured, to detect the acute changes in the inner ear after low cumulative dose of cisplatin treatment. Paired t-test, and sign test was used for statistical analysis. Results: The DPOAE did not show any changes close after cisplatin treatment (average: 2.19 cycles, 2–3 cycles), similarly to our earlier results with pure tone audiometry (PTA) and transiently evoked otoacoustic emission (TOAE). But the SOAE showed significant, early changes in incidence, shape and amplitude, in the treated group. 66% of the SOAE changed after treatment (p=0,006). In the control group (20 ears) the SOAE never changed in a three months period. (It behaves as a fingerprint) Conclusions: DPOAE did not change significantly after 2 or 3 cycles of cisplatin treatment, similarly to our earlier results with PTA, and TOAE, but the change of the SOAE-incidence, shape and amplitude close after cisplatin treatment shows acute changes in the inner ear function (first described in the literature) after administration of low cumulative dose of cisplatin. This case is the first indication of the possible clinical relevance of SOAE. Our observation has to be confirmed in further studies, with larger number of patients. No significant financial relationships to disclose.
Induction chemotherapy followed by concurrent chemoradiotherapy with/without esophagectomy for locally advanced esophageal squamous cell carcinoma
Authors: C. Lin, C. Hsu, J. C. Cheng, J. Lee, Y. Tsai, J. Luo, F. Hsu, H. Wang, Y. Lee, A. Cheng
Journal: Journal of Clinical Oncology (2009)

e15526 Background: To assess the feasibility of preoperative induction chemotherapy in addition to concurrent chemoradiotherapy (CCRT) followed by esophagectomy if possible for locally advanced esophageal squamous cell carcinoma (ESCC) with a special emphasis on M1a or nodal M1b disease. Methods: Patients who had histologic proof of T3N1M0, M1a, or nodal M1b ESCC first received up to 3 courses of induction chemotherapy (paclitaxel 70 mg/m 2 or docetaxel 40 mg/m 2 IV 1-hr D 1, 8; cisplatin 35 mg/m 2 IV 2-hr D 1, 8; 5-fluorouracil 2000 and leucovorin 300 mg/m 2 IV 24-hr D 1, 8; repeated every 28 days). This was followed by CCRT (paclitaxel 35 mg/m 2 1-hr D 1, 4 /wk, cisplatin 15 mg/m 2 1-hr D 2, 5/wk, and radiotherapy 2 Gy D 1–5 /wk) (Lin CC et al. Ann Oncol 18:93–8,2007). When the accumulated radiation dose reached 40 Gy, the feasibility of esophagectomy was evaluated in all patients. In patients for whom esophagectomy was not feasible, CCRT was continued to a dose of 60 Gy. Results: Fifty-six patients (M:F = 51:5, median age 58, range 41–78) with locally advanced (T3N1M0:M1a:M1b[nodal] = 30:7:19) ESCC (upper:mid:lower = 15:25:16) were enrolled from June 22, 2006 to December 17, 2008. By December 31, 2008, 10 patients are still under protocol treatment. Eighteen (T3N1:M1a:M1b[nodal] = 14:3:1) (40%) and 20 of 46 patients underwent surgery and continued CCRT up to 60 Gy, respectively. Nine (T3N1:M1a:M1b[nodal] = 7:2:0) (20%) and 5 patients had pathologic complete response and microscopic residual disease, respectively. With a median follow-up of 8.4 months (range 0.5–30.8), 17 (T3N1:M1a:M1b[nodal] = 9:2:6) patients had relapse. Four and 13 patients had local recurrence and distant metastasis, respectively. The median progression-free survival was 20.3 months. The median overall survival had not reached yet with 1- and 2-year overall survival being 76 and 57%, respectively. There was no difference in progression- free or overall survival among patients with T3N1M0, M1a, or nodal M1b disease. Conclusions: Three-step strategy of preoperative taxane-based induction chemotherapy then CCRT followed by esosphagectomy if possible appears quite active in locally advanced ESCC patients with 46% having M1a or nodal M1b disease. No significant financial relationships to disclose.
Treatment of metastatic melanoma with an autologous tumor-cell vaccine: clinical and immunologic results in 64 patients.
Authors: D Berd, H C Maguire, P McCue, M J Mastrangelo
Journal: Journal of Clinical Oncology (1990)

We treated 64 patients with metastatic melanoma using a melanoma vaccine preceded by low-dose cyclophosphamide (CY), and monitored immunologic effects and antitumor activity. On day 0, the patients were given CY 300 mg/m2 intravenously. Three days later, they were injected intradermally with vaccine consisting of 10 to 25 x 10(6) autologous, enzymatically dissociated, cryopreserved, irradiated (25 Gy) tumor cells mixed with bacillus Calmette-Guérin (BCG). This treatment sequence was repeated every 28 days. Of 40 assessable patients with measurable metastases, five had responses, four complete and one partial, with a median duration of 10 months (7 to 84+ months). In six additional patients, we observed an antitumor response that seems to be peculiar to this vaccine therapy: the regression of metastatic lesions that appeared after the immunotherapy was begun. Delayed-type hypersensitivity (DTH) to autologous, mechanically dissociated melanoma cells that had not been exposed to extraneous antigens, such as enzymes or fetal calf serum, increased significantly following immunotherapy (day 0 v day 49, P less than .001; day 0 v day 161, P less than .001; day 0 v day 217, P = .021). Antitumor responses to the vaccine were strongly associated with DTH, as indicated by three observations: (1) eight of 10 patients who exhibited tumor regression had positive DTH, (2) in postsurgical adjuvant patients, there was a highly significant linear relationship (P less than .001) between the intensity of DTH to autologous melanoma cells and the time to recurrence of tumor, and (3) nine patients who developed DTH to the autologous melanoma cells in their original vaccine developed new metastases that failed to elicit DTH or elicited a much smaller response. In three cases, we were able to excise regressing tumors for histologic examination; such tumors were characterized by an intense infiltration of lymphocytes. This demonstration that an immune response to melanoma-associated antigens can be elicited in cancer-bearing patients provides some basis for optimism about the prospects for developing active immunotherapy that has practical therapeutic value.
Method of renal mass reduction is a critical modulator of subsequent hypertension and glomerular injury.
Authors: K A Griffin, M Picken, A K Bidani
Journal: Journal of the American Society of Nephrology (1994)

The hypertension, proteinuria, and glomerulosclerosis that develop in the remnant kidney model (uninephrectomy plus infarction of approximately 2/3 of the other kidney) have been generally considered to represent the adverse consequences of a severe reduction in nephron number. To differentiate the blood pressure (BP) responses to infarction from those of reduced renal mass per se, BP was continuously monitored radiotelemetrically in rats whose total renal mass was reduced by 2/3 (infarction) and by 5/6 (infarction or surgical excision of both poles) and in sham-operated controls. Hypertension only developed in the two infarcted groups. Overall averages of systolic BP monitored every 10 min over 6 wk were 144 +/- 8 and 156 +/- 5 mm Hg in the 2/3 and 5/6 infarction groups (N = 10 each), respectively, as compared with 120 +/- 2 mm Hg (N = 12) in the approximately 5/6 surgical excision group (P < 0.01) and 117 +/- 5 mm Hg (N = 8) in controls. Changes in kidney weights, glomerular volumes, RBF, GFR, and renal autoregulatory ability after renal mass reduction by the two methods were qualitatively similar in additional animals from each group monitored for 2, 4, or 6 wk without radiotelemetry. Significant proteinuria and glomerulosclerosis only developed in the two infarction (hypertensive) groups. At 6 wk, 18 +/- 4 and 19 +/- 3% of the glomeruli exhibited injury in the 2/3 (N = 22) and the 5/6 infarction groups (N = 21), respectively, in contrast to 3 +/- 1% glomerular injury in the 5/6 surgical excision group (N = 24) (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)