tbuckley/cabot-search huggingface dataset:
Retrospective evaluation of GM-CSF, low-dose cyclophosphamide, and celecoxib on PSA doubling time (DT) in men with prostate cancer and PSA relapse after surgery or radiation.
Authors: M. C. Scholz, R. Y. Lam, M. A. Mendenhall
Journal: Journal of Clinical Oncology (2010)

e15061 Background: Androgen deprivation (AD) is commonly utilized to treat PSA-relapsed disease, especially in men with brisk doubling times. While AD remains effective for years, it incurs notable side effects that worsen quality-of-life such as lassitude, weight gain, osteoporosis and low libido. Less-toxic alternatives are needed. Both low-dose cyclophosphamide and celecoxib are well-tolerated and have immunomodulatory properties that may synergize with GM-CSF. Methods: 24men with hormone sensitive disease, no bone metastasis and DT < 12 months were treated with GM-CSF 500 mcg sq 3x/week, cyclophosphamide 250 mg/m2 IVPB monthly and celecoxib 200 mg PO bid. Baseline DT was established with at least 4 PSA values over a minimum of 6 months. Men treated with previous AD had recovered normal serum testosterone prior to determining baseline DT. Men treated with radiation alone were required to have a baseline PSA > 3.0. PSA was checked monthly while on Rx. Response was defined as > 100% increase in DT. Marginal response was defined a 50-100% increase in DT. Results: Medians for the 24 men: age: 72 (49-81), PSA prior to surgery or radiation: 7.95 (3.4-127), Gleason: 7 (5-9), baseline PSA at initiation of Rx: 0.95 (0.037-7.4), baseline DT: 4 mo. (2-12). Median follow-up is 16 months (5-40). Previous surgery: 14, previous radiation: 20, both: 10, previous AD: 21, documented node metastasis: 5. Most common toxicity of Rx was injection site erythema. Three men required 50% dose reduction of GM-CSF due to myalgias. Otherwise treatment was well-tolerated. Responses: 14. Marginal response: 2. Median DT on Rx for all 24 men: 12 months. For the 14 responders the baseline DT was 5 months and the DT on Rx was 24 months. Conclusions: The combination of GM-CSF, low-dose cyclophosphamide and celecoxib retards PSA progression with minimal effects on quality-of-life allowing men with PSA-relapsed disease to postpone AD for a substantial period of time. No significant financial relationships to disclose.
Interim results of a prospective, open-label, multicentre phase II trial of the efficacy and safety of vinorelbine (N) and trastuzumab (H) in patients with HER2-positive metastatic breast cancer (MBC)
Authors: M. De Wit, N. Harbeck, C. Thomssen, K. Becker, A. Psonka, R. Hoffmann, C. Villena, M. Schutte, D. K. Hossfeld
Journal: Journal of Clinical Oncology (2004)

831 Background: Preclinical data indicate that H and N have synergistic activity. This observation has prompted a number of clinical studies of this combination in women with HER2-positive MBC. H plus N has been shown to be active, producing response rates of up to 84% when used first line, and well tolerated. We are conducting a phase II study to further evaluate this combination. Methods: Women with histologically confirmed, HER2-positive (IHC 3+, or 2+ and FISH positive) MBC who had not received prior N or anti-HER2 therapy were eligible. Patients with active heart disease or with clinical manifest CNS metastases were excluded. Women received N 25mg/m2 weekly and H 4mg/kg loading dose followed by 2mg/kg weekly for at least 8 weeks and thereafter until progression. Results: 26 of a target enrolment of 32 patients have been enrolled: median age 58 (range 3175) years; median Karnofsky performance status 90% (70100). Median duration of therapy is currently 15.6 (0.129.3+) weeks; 11 patients remain on therapy. The overall response rate is 50% (2 CR, 11 PR), with 5 of 26 patients not evaluable (RR in evaluable patients, 61.9%); 2 patients had stable disease and 6 progressive disease as their best response. Treatment was well tolerated, with adverse events being mainly mild to moderate in severity and as expected based on the known side effects of these agents: fatigue 50%; nausea 34.6%; diarrhoea 23.1%; vomiting 19.2%. The majority of patients experienced neutropenia (53.8%), anaemia (76.9%) or leucopenia (73.1%); 6 patients had grade 3 or 4 neutropenia. 6 patients experienced 10 serious adverse events, including 2 infusion-related reactions and 2 cases of dyspnoea with the initial trastuzumab infusion, and one decrease in LVEF to below 50%. Conclusions: This interim analysis of a phase II study of H and N supports previous trials demonstrating that this combination is an effective and well-tolerated regimen for the treatment of women with HER2-positive metastatic breast cancer. Enrolment continues and updated data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche
Cardiovascular adverse events during adjuvant endocrine therapy for early breast cancer using letrozole or tamoxifen: Updated safety analysis of trial BIG 1–98
Authors: A. S. Coates, H. Mouridsen, Z. Sun, M. Rabaglio, M. Castiglione-Gertsch, B. Thürlimann, L. Mauriac, K. N. Price, M. Colleoni, I. Smith
Journal: Journal of Clinical Oncology (2007)

521 Background: Studies of aromatase inhibitors (AI) vs. tamoxifen (T) including the BIG 1–98 study have suggested a small numerical excess of cardiac adverse events (AEs) and increased incidence of hypercholesterolemia on AIs, and significantly higher incidence of thromboembolic AEs on T. Methods: 8,028 postmenopausal women with receptor-positive early breast cancer were randomized (double-blind) between March 1998 and May 2003 to receive 5 years letrozole (L), T, or a sequence of these agents. 7,963 patients who actually received therapy are included. AEs were recorded through 30 days after therapy completion or after switch on the sequential arms. Cardiovascular AEs were prospectively collected and graded. Cholesterol measurements were analyzed for percent change in total cholesterol from baseline by follow-up visit. Cox proportional hazards models were used to compare T and L according to time to first cardiovascular AE, adjusting for hypercholesterolemia at baseline or prior to the event, age, BMI, and history of smoking, hypertension, diabetes, and cardiac morbidity. The median follow-up was 30.1 months. Results: Baseline co-morbidities were balanced. Cox model results for time to first grade 3–5 cardiovascular AE are below. Cholesterol values decreased over time on both treatments, but to a greater extent and earlier on T. Conclusion: Taken together, cardiovascular AEs were relatively rare, and any excess of cardiac events on L seems to be outweighed by the superior control of recurrence afforded by L compared to T. An understanding of the nature, frequency and mechanism of such AEs is important to the optimization of the therapeutic ratio in adjuvant endocrine therapy with AIs. [Table: see text] No significant financial relationships to disclose.
Abstract 15404: Efficient and Persistent Transgene Expression by Minicircle Plasmid versus Standard Plasmid Using Ultrasound Targeted Microbubble Destruction
Authors: Dmitriy Rudenko, Pratiek N Matkar, Saleh A Alghadeer, Christine Liao, Hao H Chen, Michael A Kuliszewski, Howard Leong-Poi
Journal: Circulation (2014)

Background: Ultrasound-targeted microbubble destruction (UTMD) is a non-invasive gene transfection technique using carrier microbubbles and targeted high power ultrasound, primarily used to deliver plasmid DNA (pDNA). Minicircle-DNA (mcDNA) is a novel gene vector, which has recently been shown to have an improved and persistent transfection, compared to conventional pDNA. Hypothesis: We hypothesized that UTMD of mcDNA in a hind-limb model would exhibit a more potent and prolonged gene expression compared to conventional pDNA. Methods: In vitro , HUVECs, fibroblasts (3T3) and neonatal cardiomyocytes were transfected with molar equivalents of GFP-minicircle and GFP-plasmid. GFP expression was measured by RT-PCR and fluorescent microscopy for 28 days. We then performed a comparison of bubble binding capacities of both vectors to cationic lipid microbubbles. In vivo , for UTMD to the left proximal hind-limb adductor muscle, 500μg and 214μg of GFP-plasmid and GFP-minicircle respectively were charge-coupled with 1x10 9 cationic microbubbles and delivered via UMGD into Sprague-Dawley rats (n=30). The animals were followed for 28 days with GFP measured by RT-PCR and immunohistochemistry. Results: In vitro results showed greater GFP expression by mcDNA across all cell lines, with 7-10 fold transfection efficacy compared to pDNA. mcDNA demonstrated greater binding capacity to cationic microbubbles compared to pDNA. For plasmid and minicircle DNA, binding saturations were reached at ~6000 copies per microbubble, and ~20000 copies per microbubble respectively, suggesting a higher minicircle bubble binding efficiency. In vivo results showed higher GFP levels as early as 6 hours post minicircle UTMD, demonstrating minicircle to be a faster acting therapeutic agent over conventional plasmid. A significantly greater (p&lt;0.01) expression of GFP was also evident at day 28 in minicircle UTMD-treated group, proving mcDNA to be a better choice for longer-term gene expression. Conclusions: In summary, UTMD using mcDNA results in more rapid and sustained transfection compared to conventional pDNA, and may be a more effective vector for translational studies of UTMD.
The influence of patient and companion cure expectations on treatment decisions
Authors: M. E. Gleason, F. W. Harper, S. Eggly, J. C. Ruckdeschel, T. L. Albrecht
Journal: Journal of Clinical Oncology (2008)

9568 Background: The purpose of this study was to investigate how cancer patients’ expectations for cure influence their decisions to follow their oncologist’s treatment recommendations and whether matched expectations for cure between patients and their companions (if present) independently influence patient treatment decisions. Methods: Prior to meeting with MDs, PTs and CPs completed background questions about whether they expected the PT’s cancer would be cured or not. PTs and CPs subsequently met with MDs to discuss treatment. Within two weeks of the interaction, PTs completed a telephone survey about whether they intended to follow MD treatment recommendations (NO, MAYBE, or YES). Results: 102 patients (PT) participated in the study, 78 of which were accompanied by at least one person (max = 4) resulting in participation of 116 companions (CP). 59% of PTs were male, 29% of CPs were male. The majority of PTs (78%) and CPs (89%) were Caucasian. CPs were spouses (47%), adult children (28%), “other” (9%), friends (6%), siblings, (5%), or parents (4%). 55 PTs (54%) did not expect a cure; analyses showed that PT expectations for cure did not directly influence PT treatment decisions (Bexpectation=−0.02, ns). In addition, 70 CPs (60%) did not expect a cure. Two-thirds of the PT-CP groups held matched expectations about the PT’s potential for cure; 40% of those who matched expected a cure, and 60% did not. Analyses showed that PTs were less likely to follow treatment recommendations when, prior to meeting with the MD, PTs’ expectations matched CPs’ expectations for cure regardless of whether PTs and CPs believed the PT would be cured or believed the PT would not be cured (Bmatching=−0.28, p=0.05). Conclusions: Cancer PTs’ expectations about whether they would be cured did not directly affect their decision to follow their MD treatment recommendations. Rather, the expectation-decision relationship was moderated by the extent to which PT expectations are the same as CP(s). To better understand patient treatment decisions, researchers should consider the complex ways in which PTs’ and their CPs’ expectations about cure affect PT decisions about treatment. No significant financial relationships to disclose.
A comparison of regimens for preoperative chemotherapy in a group of Chinese breast cancer patients
Authors: X. Huang, J. Tang, J. Feng, L. Zhang, L. Pan, J. Chen, J. Qin
Journal: Journal of Clinical Oncology (2008)

11566 Background: Preoperative chemotherapy for Chinese patients with breast cancer has been conducted for more than 20 years in China. However, few clinical trials showed comparison among several commonly used regimens regarding to their response rates in mainland China. Methods: From Oct 1995 to Aug 2007, 462 Chinese breast cancer patients in Jiangsu Province, who were pathologically confirmed with adenocarcinoma received preoperative chemotherapy. After 2 to 4 cycles of cyclophosphamide, methotrexate and 5-fluorouracil (CMF), doxorubicin, taxanes or vinorelbine based chemotherapy, patients were surgically treated. Eleven patients were exposed to CMF, 252 to 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), 67 to cyclophosphamide, doxorubicin and cisplatin (CAP), 22 to 5-fluorouracil, doxorubicin and cisplatin (FAP), 61 to vinorelbine and cisplatin (NP), and 49 to docetaxel, doxorubicin, and cyclophosphamide (TAC). Results: Tumor response rate (RR) defined by WHO criteria was 54.5% for CMF, 71.8% for FAC, 70.2% for CAP, 77.3% for FAP, respectively. Vinorelbine containing regimen achieved 91.8%, and taxanes achieved 91.8% RR, respectively. RRs of vinorelbine or taxanes containing regimen are higher than rest regimens with statistical significance. Conclusions: Preoperative chemotherapy significantly reduced tumor size so that resection rate was increased and conserving surgery was possible. With regard to response rate, taxanes or vinorelbine based regimens are superior to CMF, FAC, CAP or FAP in this group of Chinese patients. No significant financial relationships to disclose.
Pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in early-stage NSCLC
Authors: G. Schmid-Bindert, A. Chemaissani, J. R. Fischer, W. Schütte, J. Mazières, N. Viñolas, M. Wolf, A. Thareau Vaury, M. Leschinger, M. Reck
Journal: Journal of Clinical Oncology (2009)

7565 Background: Platinum based chemotherapy after complete resection of stage I-IIIa non-small cell lung cancer (NSCLC) has improved 5-yr survival by 4–15%. Pemetrexed (P) in combination with cisplatin (C) or carboplatin (Carb) has shown to be effective and safe in first-line Tx of advanced NSCLC, thus being a promising option in the adjuvant setting. Methods: Multicenter, open phase 2 in pts with resected stage Ib/II NSCLC. Pts were randomized to P (500 mg/m 2 )+C (75mg/m 2 ) or P (500 mg/m 2 )+Carb (AUC5) d1 q3 wks, for 4 cycles; adequate organ function and ECOG PS 0–1 required. Primary endpoint was feasibility of the regimen defined as compliance to 4 Tx cycles with ≥ 95% of planned dose without ≥ Grade 3 toxicities (tox) at 30 d after last infusion. A regimen was deemed feasible if the rate (feasible pts/total pts) was &gt;60%. Results: Please see Table for results. Conclusions: According to the strict definitions in this protocol neither regimen was feasible. The reason was poor compliance with at least one of the components that defined feasibility, but dose intensity and % pts completing cycle 4 was notably high, compared to other adjuvant trials. P+C was the more favourable regimen concerning feasibility and tolerability. In terms of tolerability pemetrexed could be combined with either platinum compound. [Table: see text] [Table: see text]
Single nucleotide polymorphisms in <i>FAS</i> and <i>FASL</i> and sensitivity to gefitinib in patients with advanced non-small cell lung cancer.
Authors: F. Ma, Y. Liao, W. Zi-Ping, B. Xu
Journal: Journal of Clinical Oncology (2010)

e13529 Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) play a key role in the management of advanced non-small cell lung cancer (NSCLC). Numerous investigations have demonstrated an association between the presence of somatic mutations in EGFR and the sensitivity to gefitinib or erlotinib in NSCLC. Since genetic polymorphisms are more prevalent than mutations in human genome, some of them may be more practical as genetic biomarkers to predict the sensitivity to EGFR-TKIs. The FAS-FASL system plays crucial role in apoptotic signaling in many tumor cells. Here, we assessed the possibility that single nucleotide polymorphisms (SNPs) in FAS and FASL could be used to predict the sensitivity to gefitinib in patients with advanced NSCLC. Methods: Candidate polymorphic loci approach was used to determine the functional polymorphisms. SNPs in the promoter region of the FAS (−1377G/A and −670A/G) and FASL (−844T/C) were assessed in 88 advanced NSCLC patients treated with gefitinib. The Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The association between genotypes and sensitivity to gefitinib was validated by statistical tests. Results: For FAS -1377G/A, the clinical benefit rates (CBR) of gefitinib in advanced NSCLC patients were 31.3%, 61.1% or 74.3% (p = 0.014) in AA, GA or GG genotypes, respectively. For FAS −670A/G, the CBR were 32.0%, 78.0% or 57.9% (p = 0.001) in GG, AG or AA genotypes. For FASL - 844T/C, the CBR were 65.2%, 57.1% or 50% (p = 0.276) in CC, CT or TT genotypes. FAS -670 GG genotype carriers also had a significantly shorter survival time after the treatment of gefitinib than variation allele carriers (AG or AA genotypes), the overall survival time were 26 and 47 months (p = 0.012), respectively. Conclusions: FAS -1377G/A and -670A/G polymorphisms may be predictive for sensitivity to gefitinib in patients with advanced NSCLC. No significant financial relationships to disclose.
Morphologic and Microspectrophotometric Studies on Spontaneous Melanomas in Xiphophorus helleri
Authors: Takatoshi Ishikawa, Koko Sakakibara, Katsumaro Kurumado, Hiroyuki Shimada, Kazuyoshi Yamaguchi
Journal: JNCI Journal of the National Cancer Institute (1975)

Melanomas developed in both sexes of a strain of Tuxedo variety of the swordtail (Xiphophorus helleri) at a relative frequency of 10-15%. They did not metastasize. However, the tumor margin had infiltratitive growth and subsequently ulcerated. This feature, together with the histologic and cytologic features and apparent heteroploidy of the tumors, as revealed by their DNA content, indicated that the tumors were indeed neoplastic. Electron microscopic findings on the melanosomes in these melanomas at various stages of development were comparable with those on the Harding-Passey mouse melanoma, which contains granular premelanosomes.
Bcl-2 overexpression attenuates apoptosis induction by sulindac sulfide in SW480 human colon cancer cells
Authors: R. Penington, F. Sinicrope
Journal: Journal of Clinical Oncology (2004)

3195 Background: Sulindac sulfide is a NSAID and an inhibitor of cyclooxygenase enzymes that regulate prostaglandin synthesis. Sulindac is a potent chemopreventive agent in animal models of colon cancer and in patients with familial adenomatous polyposis. Sulindac sulfide induces apoptosis in colon cancer cells which may be an important mechanism of its anti-tumor effects. Previously, we found that sulindac sulfide can modulate both the caspase-8-depedent and cytochrome c-dependent apoptotic pathways. We determined whether Bcl-2 overexpression, an inhibitor of the latter apoptotic pathway, can inhibit apoptosis induction by sulindac sulfide. Materials and Methods: SW480 cells were stably transfected with the pC3-Bcl-2 plasmid (SW480/Bcl-2) or vector alone (SW480/neo). The level of Bcl-2 protein expression was then determined by immunoblotting (anti-Bcl-2 antibody, Upstate). Cells were incubated with sulindac sulfide (0–120 μM) for 72 hr and then floating and attached cells were harvested and assayed for Annexin V-FITC (BD PharMingen) labeling by flow cytometry. The effect of a caspase-9 inhibitor (Z-LEHD-FMK, R & D Systems) or a caspase-8 inhibitor (Z-IETD-FMK, R & D Systems) upon sulindac sulfide-induced apoptosis was also studied. Results: SW480/Bcl-2 cells showed overexpression of Bcl-2 proteins relative to SW480/neo cells. Bcl-2 overexpression produced an anti-apoptotic effect (>50% reduction) compared to SW480/neo control cells, as assayed by Annexin V binding after incubation with sulindac sulfide (72 hr). Furthermore, co-treatment with a caspase-9 inhibitor significantly reduced the Annexin V binding (>50%) triggered by sulindac sulfide treatment. A caspase-8 inhibitor was also found to significantly reduce Annexin V binding (>50%) in sulindac sulfide-treated parental cells. Conclusion: Sulindac sulfide engages both the caspase-8- and caspase-9-dependent apoptotic signaling pathways in SW480 cells. Bcl-2-mediated inhibition of apoptosis by sulindac sulfide indicates that Bcl-2 is an important modulator of the therapeutic efficacy of this agent used for the prevention or treatment of human colon cancer. No significant financial relationships to disclose.
Biological characteristics of oestrogen receptor positive early operable primary breast cancer in the elderly
Authors: M. W. Ying, A. R. Green, A. Agrawal, C. E. Paish, D. A. Morgan, I. O. Ellis, K. L. Cheung
Journal: Journal of Clinical Oncology (2006)

10739 Background: Over half of breast cancer are diagnosed at &gt;65 years and increasingly more are diagnosed in the elderly population. However little is known about their biological characteristics, which may be important in therapeutic strategies such as selecting endocrine agents as primary, neoadjuvant or adjuvant therapy. We report the pattern of oestrogen receptor (ER), progesterone receptor (PgR) and HER2 status in a cohort of elderly patients with primary breast cancer (PBC). Methods: All elderly (&gt; 70 years) patients, who had ER positive early operable PBC (&lt; 5 cm) and who refused or were unfit for surgery, were treated with primary endocrine therapy. Standard immunohistochemical staining was performed on core biopsy tumour tissuefor ER, PgR and HER2. Positivity for ER and PgR was defined by H-score ≥ 50, and HER2 positivity was defined as 3+. Results: A total of 86 such patients were treated over a two-year period and the biological characteristics of their tumours were as follows (see Table ). Conclusions: Within the group of ER positive patients, approximately half of the tumours also expressed PgR. The total number of HER2 positive tumours was small although the majority of these were PgR negative. Clinical follow-up is ongoing to elucidate the relationship between endocrine sensitivity and these biological characteristics. [Table: see text] [Table: see text]
Abstract 4035: Left Ventricular Geometry and Mortality Prediction by Different Indexation Methods for Left Ventricular Mass by Obesity Status in 47,865 Patients
Authors: Dharmendrakumar A Patel, Carl J Lavie, Richard Milani, Hector Ventura
Journal: Circulation (2009)

Echocardiographically determined LV mass (LVM) is often indexed to body surface area (BSA), but this may not accurately characterize the influence of obesity on LVM and related mortality. We evaluated 18,630 obese (BMI ≥30; age: 59±14 yr) as well as 29,235 non-obese (BMI  40 kg/m2) obesity. However, the LVM/BSA method had higher mortality in CR, EH and CH compared with the LVM/Ht2.7 method, especially in obesity. In conclusion:



1.  Subtle differences in the classification of LV geometry exist between the two LVM indexing methods was noted, particularly in patients with more marked degrees of obesity.

2.  LV geometric classifications using LVM corrected by either BSA or Ht2.7 predict mortality, both in obese and non-obese patients.





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Tolerability of sunitinib in combination with docetaxel and trastuzumab as first-line therapy for HER2+advanced breast cancer : Abstract #4120
Authors: F. Cardoso, J-L. Canon, D. Amadori, L. Dirix, E. Villa, D. Aldrighetti, Jean-Pascal Machiels, L. Verkh, X. Huang, C. Giorgetti
Journal: Cancer Research (2009)