tbuckley/cabot-search huggingface dataset:
Combined modality treatment for breast cancer: Justification for integration of transplants at diagnosis
Authors: P. Hupperets, M. E. Van Hoef
Journal: Journal of Clinical Oncology (2006)

10760 &gt;Introduction: In acute leukemia best therapy consist of fast remission-induction, consolidation of complete response and allogeneic transplantation to eradicate residual malignant cells. This therapeutic plan at diagnosis consists of three treatment combinations that have been proven to be most efficacious when administered consecutively according to protocol. Methods: The three treatment combinations were defined as independent entities and literature search was pursued to identify equivalent components for high risk and metastatic breast cancer. Results were tabulated. Results: First line combination treatment induces complete response rates that can be enhanced by dose density. This type of intensification does not change the risk of relapse although time to relapse may vary by a few months; survival in high risk breast cancer is about 50% and in early metastatic 10%. Failure to treat more aggressively induces respectively 50% and 90% relapse mortality. It is hidden treatment-failure related mortality. High-dose autologous transplants (HD-auto-tx) add a survival advantage of about 10% but this is statistically not considered significant. In large series treatment related mortality (TRM) of HD-auto-tx is 0–3%. Treatment integrating autologous transplantation reduce relapse mortality to respectively 60% and 80%. Allogeneic transplants induce an immune response in breast cancer that is comparable to the response observed in leukemia; micrometastatic bone marrow disease can be eradicated. After an autologous transplant risk of relapse is 80% and after an allogeneic transplant in first consolidated remission 20%. Allogeneic transplants make the combination attractive, despite the risk of TRM, mainly attributable to graft versus host disease. Selection of right treatment schedules and adequate prophylaxis for and treatment of graft versus host disease is emerging and may minimize the risk of TRM as result of this side effect to &lt;5%. Discussion: Optimization of treatment by integration of transplants in treatment at diagnosis is warranted to offer breast cancer patients the choice of cure at certain risks versus the standard chemotherapy resulting in remarkably higher disease driven mortality. Details will be presented. No significant financial relationships to disclose.
CNS involvement in mantle-cell lymphoma.
Authors: E Montserrat, F Bosch, A López-Guillermo, F Graus, M J Terol, E Campo, C Rozman
Journal: Journal of Clinical Oncology (1996)

PURPOSE In non-Hodgkin's lymphomas, CNS involvement is highly dependent on the histology of the lymphoma. Mantle-cell lymphoma (MCL) is a lymphoma type with distinctive histologic, biologic, and clinical features in which CNS involvement has only been rarely described. The purpose of this report is to describe the incidence, clinical characteristics, and outcome of CNS infiltration in patients with MCL seen at a single institution. PATIENTS AND METHODS Twenty-two patients with MCL, who account for 6% of all patients with nodal lymphomas diagnosed and monitored at a university hospital from 1987 to 1994, were studied. Analysis of the incidence of CNS involvement by the disease was performed. RESULTS Five of 22 patients (22%; exact 95% confidence interval [CI], 7.8% to 45.4%) with MCL developed CNS involvement at a median of 18 months (range, 6 to 59) from diagnosis. All of these patients presented with poor MCL histologic subtypes and advanced disease. When the CNS infiltration became apparent, all of the patients displayed neurologic signs and had lymphoid cells consistent with the diagnosis of MCL in the CSF. In most of the cases, CNS infiltration was part of resistant disease or generalized relapse and had an ominous significance. CONCLUSION The incidence of CNS involvement in MCL might be higher than previously recognized. The frequency of CNS infiltration in MCL deserves to be investigated in other series and, if a high incidence is confirmed, the risk factors, mechanisms, and clinical implications of such a complication should be further studied.
The prognostic analysis of gastrointestinal stromal tumor
Authors: Y. Shi, C. Du, H. Fu, G. Zhao, y. Zhou
Journal: Journal of Clinical Oncology (2007)

20534 Objective: To investigate the prognostic factor of gastrointestinal stromal tumor. Methods: The clinicopathological data of 103 patients with gastrointestinal stromal tumors were analyzed restrospectively. Life table, kaplan-meier survival rate and cox regression model were used to evaluate the prognostic factors. Results: The 1 year ,3 years and 5 years total survival rate of these 103 gastrointestinal stromal tumors was 86.3%, 51.7%, 42.8%. Tumor size, mitotic rate, primary organ of tumor and radical surgical excision or not were analyzed respectively, the difference is statistical significance (P&lt;0.05). No significiant difference between the group of sex, age, immunohistochemistry expression and multi-organ resection or not. Conclusion: Flechers’ classification is rational, scientific, simple and feasible. Radical surgical excision is the best therapy to the primary gastrointestinal stomal tumor. No significant financial relationships to disclose.
ABC-03: A randomized, phase II/III study of cediranib (AZD2171) or placebo in combination with cisplatin/gemcitabine for patients with advanced biliary tract cancers.
Authors: J. W. Valle, J. A. Bridgewater, M. Roughton, C. Dive, S. Hughes, H. S. Wasan
Journal: Journal of Clinical Oncology (2010)

TPS218 Background: The ABC-02 trial (Valle ASCO 2009, abstr. 4503), the largest ever randomized phase III trial in ABC to date, demonstrated a significant survival advantage for GemCis over Gem alone (11.7 vs. 8.2 months [log rank p=0.002], with hazard ratio 0.68 [95%-CI 0.53, 0.86]) without added clinically significant toxicity. ABCs are associated with an increase in VEGF expression, which in turn correlates with the presence of metastatic disease. Cediranib is a highly potent inhibitor of VEGFR2 tyrosine kinase and VEGF-induced signaling in endothelial cells. Cediranib is expected, at chronic oral dosing, to inhibit VEGF driven angiogenesis and, as a consequence, constrain tumor growth. ABC-03 compares GemCis with either cediranib or with placebo. This randomized phase II trial, will recruit 136 pts, with progression-free survival (PFS) as the primary endpoint. Methods: Consenting pts with histologically/cytologically confirmed ABC, aged ≥18 years, ECOG performance status 0-2 and adequate haematological, hepatic, and renal function will be randomized to receive Cis (25 mg/m2) followed by Gem (1000 mg/m2) d1, 8 q21d, plus either placebo (OD) or cediranib (20mg OD) for up to 8 cycles. All pts will be imaged for PFS at 12 and 24 weeks. Cediranib/placebo will continue until evidence of disease progression has been identified. The trial is designed to compare PFS between the two treatment arms, with 80% power (alpha=0.2, two-sided) and to detect a PFS hazard ratio (HR) of 0.64. This requires a sample size of 68 pts per arm. Biomarker evaluation (including circulating tumor cells, circulating VEGF, sVEGFR-2, bFGF, LDH and CA19-9) will also be performed on all pts. Accrual to this trial will commence in June 2010. No significant financial relationships to disclose.
Cell-selective arrhythmia ablation for photomodulation of heart rhythm
Authors: Uma Mahesh R. Avula, Hyung Ki Yoon, Chang H. Lee, Kuljeet Kaur, Rafael J. Ramirez, Yoshio Takemoto, Steven R. Ennis, Fred Morady, Todd Herron, Omer Berenfeld, Raoul Kopelman, Jérôme Kalifa
Journal: Science Translational Medicine (2015)

Heart disease, a leading cause of death in the developed world, is overwhelmingly correlated with arrhythmias, where heart muscle cells, myocytes, beat abnormally. Cardiac arrhythmias are usually managed by electric shock intervention, antiarrhythmic drugs, surgery, and/or catheter ablation. Despite recent improvements in techniques, ablation procedures are still limited by the risk of complications from unwanted cellular damage, caused by the nonspecific delivery of ablative energy to all heart cell types. We describe an engineered nanoparticle containing a cardiac-targeting peptide (CTP) and a photosensitizer, chlorin e6 (Ce6), for specific delivery to myocytes. Specificity was confirmed in vitro using adult rat heart cell and human stem cell-derived cardiomyocyte and fibroblast cocultures. In vivo, the CTP-Ce6 nanoparticles were injected intravenously into rats and, upon laser illumination of the heart, induced localized, myocyte-specific ablation with 85% efficiency, restoring sinus rhythm without collateral damage to other cell types in the heart, such as fibroblasts. In both sheep and rat hearts ex vivo, upon perfusion of CTP-Ce6 particles, laser illumination led to the formation of a complete electrical block at the ablated region and restored the physiological rhythm of the heart. This nano-based, cell-targeted approach could improve ablative technologies for patients with arrhythmias by reducing currently encountered complications.
Restenosis Following Mitral Valvoplasty
Authors: G W THOMAS, W G BIGELOW
Journal: JAMA (1963)

Nineteen seriously disabled patients were operated upon a second time (using closed-heart technique) for recurrence of symptoms of mitral stenosis. The hospital mortality rate was 10.5%; there was one late death. Ten patients (52%) were well and working six months to five years after the second operation. In considering the cause of restenosis it was noted that nine patients had inadequate opening of the mitral valve at first operation. In five cases (26%) rheumatic activity appeared to be solely responsible for restenosis. In a further four cases (21%) it was considered that rheumatic activity was a contributing cause of restenosis. The diagnosis of rheumatic activity and the place of open heart procedures in the treatment of restenosis are discussed.
Mode of tumor penetration of intravenously administered liposomal doxorubicin
Authors: Xing Q. Pan, S. Jones, K. Cox, H. Zhang, Pan Zheng, Manohar Ratnam, R. Lee
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

3847 

The use of liposomes as vehicles to transport anticancer drugs to increase drug effectiveness and decrease toxicity has been studied for several decades. A large number of reports on the uptake of liposome particles by tumor cells in vitro and dispersion in solid tumor have been published. However, since liposome particles are not stable under the conditions of the regular procedures of tissue staining, the standard methodologies have not clearly demonstrated the exact process by which liposome particles penetrate solid tumor tissue. In this study, we used rhodamine-labeled latex microspheres that mimic the particle size (100 nm) and electric charge of liposome particles as well as DSPC pegylated liposomal doxorubicin to visualize pentration of nanoparticles into solid tissue tumors. Solid tumors of L1210 cells transplanted subcutaneously in DBA2 mice and human oral carcinoma cells transplanted in SCID mice were used as animal models in this study. After i.v. injection through the tail vein, tumor tissue samples were collected at different time points, and immediately embedded in O.C.T. Cryosections (0.6 μm) of this sample were stained using anti-mouse CD31 to localize endothelial cells in blood vessels which were visualized by the green fluorescence of a FITC-streptavidin-biotin system. In these sections, the blue fluorescence of the dye DAPI was used to identify the nuclei of the tumor cells. Red fluorescent liposomal particles or rhodaminine-labeled latex microspheres were also readily detected in the sections under a fluorescent microscope. The results showed that the model nanoparticles could only enter the tumor tissue at certain foci presumably representing leaky sites in the blood vessels and spread locally. The findings could be used to explain the observed differences in anticancer effectiveness among tissue-targeted liposomal doxorubicin, non-targeted liposomal doxorubicin and free doxorubicin.
Phase II breast cancer chemoprevention trial of the third generation selective estrogen receptor modulator arzoxifene
Authors: C. J. Fabian, B. F. Kimler, J. R. Anderson, C. Chamberlain, M. S. Mayo, C. M. Zalles, J. A. O’Shaughnessy, H. T. Lynch, K. A. Johnson, D. Browne
Journal: Journal of Clinical Oncology (2006)

1001 Background: Arzoxifene (ARZ) is a third generation SERM with efficacy in metastatic breast cancer but lacking uterine agonist activity. Methods: We conducted a randomized, double-blind, placebo-controlled Phase II prevention trial in 199 high risk women assessing the effects of ARZ 20 mg/day on several risk biomarkers. Biomarkers, including cytomorphology of breast epithelial cells obtained by random periareolar FNA (RPFNA) were assessed at baseline and following 6 months of placebo or ARZ. Subjects were stratified by presence or absence of atypia, ER expression, BRCA1/2 mutation, as well as menopause status. Results: At entry, mean age was 47, 52% were premenopausal and 47% of postmenopausal women were taking HRT. Mean 10 year Gail was 6.8% and mean Masood cytology index score was 14.3. The ARZ and placebo groups were well matched. The protocol defined primary endpoint was a decrease in RPFNA cytology Masood index score by ≥3 points at 6 months and required 160 evaluable subjects for 81% power to detect a change from 30% to 52% of subjects showing improvement. For the 181 evaluable subjects, there was no significant difference in the proportion of women achieving ≥3 point improvement (19% placebo vs. 24% ARZ, p=0.46); or in change in mean index score (0.6 placebo vs. 0.9 ARZ, p=0.53). There was also no difference in grade 3 or 4 side effects or dropout prior to 6 months. However, comparing ARZ to placebo, there was favorable modulation of the two risk biomarkers, mammographic breast density (p=0.001) and IGF-1:IGFBP-3 ratio (p=0.001), and reduction in bone turnover biomarker osteocalcin (p= 0.002), but without an increase in endometrial thickness. Conclusions: Although improvement in cytomorphology after 6 months of ARZ was not shown, the acceptable side effect profile and favorable modulation of other biomarkers (breast density, IGF-1:IGFBP-3, osteocalcin) provides support for continued evaluation of ARZ as a breast cancer prevention agent. No significant financial relationships to disclose.
Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): Results from the phase III study ENDEAVOR.
Authors: Meletios A. Dimopoulos, Philippe Moreau, Antonio Palumbo, Douglas E Joshua, Ludek Pour, Roman Hajek, Thierry Facon, Heinz Ludwig, Albert Oriol, Hartmut Goldschmidt, Laura Rosinol, Jan Straub, Aleksandr Suvorov, Carla Araujo, Tomas Pika, Gianluca Gaidano, Katja Weisel, Vesselina Goranova-Marinova, Heidi H. Gillenwater, Wee Joo Chng
Journal: Journal of Clinical Oncology (2015)

8509 Background: ENDEAVOR (NCT01568866) is comparing Kd with Vd in pts with RMM. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), overall response rate (ORR), rate of peripheral neuropathy (PN), and safety. Methods: Adults with RMM and 1-3 prior treatments were eligible; planned enrollment was 888 pts. Pts were randomized 1:1 and stratified by prior K or V (yes vs no), prior lines of treatment (1 vs 2-3), ISS stage (1 vs 2-3), and intended route of V (IV vs SC). The Kd arm received K (30-min IV infusion) on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (20 mg/m2 on D1 and 2 [cycle 1]; 56 mg/m2 thereafter) and dexamethasone (dex; 20 mg) on D1, 2, 8, 9, 15, 16, 22, and 23. The Vd arm received V (1.3 mg/m2; IV or SC on D1, 4, 8, and 11 of a 21-day cycle) and dex (20 mg) on D1, 2, 4, 5, 8, 9, 11, and 12. Cycles were repeated until disease progression or unacceptable toxicity. Results: Data are presented for Kd then Vd. In total, 929 pts (Kd: 464; Vd: 465) from 27 countries were randomized. In the Vd arm, 83.6% of pts received SC V. At the preplanned interim analysis, median treatment exposure was 39.9 and 26.8 weeks. Kd showed a significant improvement in median PFS vs Vd (18.7 months [mo] vs 9.4 mo; hazard ratio = 0.53; P< .0001). OS data were immature (75 and 88 deaths) and continue to be followed. ORRs were 76.9% and 62.6% (P< .0001); 54.3% and 28.6% had a very good partial response or better, and 12.5% and 6.2% of pts had a complete response or better. Treatment discontinuation due to an adverse event (AE) occurred in 14.0% and 15.7% of pts. On-study death due to an AE occurred in 3.9% and 3.4% of pts. AEs of interest (grade ≥ 3) included hypertension (preferred term; 8.9% vs 2.6%), dyspnea (high-level term; 5.6% vs 2.2%), cardiac failure (grouped term; 4.8% vs 1.8%), and acute renal failure (grouped term; 4.1% vs 2.6%). Rates of grade ≥ 2 PN (grouped term) were 6.3% vs 32.0% (P< .0001). Conclusion: Kd demonstrated statistically significant and clinically meaningful superiority over Vd in RMM, with a two-fold improvement in median PFS. In addition, Kd had a favorable benefit-risk profile. These data suggest that K is a potential best-in-class agent for RMM. Clinical trial information: NCT01568866.
Immunological results of a phase II randomized trial of multipeptide vaccines for melanoma
Authors: C. L. Slingluff, G. Petroni, K. A. Bullock, E. Bissonnette, S. Hibbitts, C. Murphy, N. Anderson, W. W. Grosh, P. Y. Neese, R. Fink
Journal: Journal of Clinical Oncology (2004)

7503 Background: To evaluate the immunogenicity of 12 peptides from cancer-testis and melanocyte differentiation proteins, and to assess the feasibility of complex peptide vaccines, a randomized phase II trial was performed in 51 patients with resected high-risk melanoma. Methods: Arm 1 received 4 peptides and arm 2 received 12 peptides. Each vaccine was an emulsion of 4 or 12 peptides (100ug each), a tetanus helper peptide (190ug), Montanide ISA-51 adjuvant (1 ml), and GM-CSF (110 ug). T-cell responses were evaluated in peripheral blood lymphocytes and in a sentinel immunized node by IFNγ ELIspot assay after one in vitro sensitization. Results: All patients have completed treatment; immunologic assessment is complete on 31 patients. Preliminary data from these 31 patients reveal immune responses in 11/14 patients (79%) on arm 1 and 17/17 patients (100%) on arm 2. Responses to 9 of the peptides are shown (Table). Patients on arm 2 responded to an average of 2.8 different peptides, those on arm 1 responded to an average of only 0.9 peptides. By comparing T cell responses to three index peptides in both peptide mixtures, it will be possible to assess whether co-administration of 4 peptides binding the same MHC molecule interferes with immunogenicity of the index peptides. Current results indicate that the median of the best immune responses for index peptides (fold-increase over background) was 9.7 in arm 1 and 11.1 in arm 2. The mean number of responses to index peptides per patient was 0.7 for Group 1, and 1.1 for Group 2. Conclusions: These findings support that (1) the most immunogenic peptides in this study were from tyrosinase, gp100, MAGE-A1, and MAGE-A10; (2) multiple peptides can be administered in combined aqueous mixture with safety and immunogenicity, and (3) immunogenicity is maintained despite peptide competition for binding to MHC. Further investigation of multiple-peptide vaccine mixtures is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration This was funded primarily by the NCI (R01 CA57653), but funding was provided by Immunex for purchase of GMCSF used in the vaccines
A phase II trial of LY317615 in patients with recurrent high grade gliomas
Authors: H. A. Fine, L. Kim, C. Royce, S. Mitchell, J. P. Duic, P. Albert, L. Musib, D. Thornton
Journal: Journal of Clinical Oncology (2004)

1511 Background: Gliomas are amongst the most angiogenic of all solid tumors and experimental evidence suggests that angiogenesis inhibition can be an effective approach for inhibiting glioma growth in vivo. PKC-β2 is an important signaling molecule in the induction of, and signaling through the VEGF pathway, thus making PKC-β2 an attractive therapeutic target. LY317615 is a macrocytic bisindolylmaleimide which disrupts the intrinsic phosphotransferase activity of conventional and novel PKC isoforms via an interaction at the ATP binding site and displays selectivity in inhibiting the beta isoform. Preclinical studies demonstrate potent antiangiogenic activity of LY317615. A normal volunteer and a phase I trial in solid tumor patients (pts) demonstrate the drug is very well tolerated at doses that achieve a biologically active serum concentration. Based on the dependence of glioma growth on VEGF-mediated angiogenesis, and the promising preclinical and clinical data, we have initiated a phase II trial of LY317615 in pts with recurrent and progressive high grade gliomas following standard therapy. Methods: Treatment consists of oral LY317615 administered daily on an every 6 week cycle after which pts undergo a complete physical/neurological, biochemical and radiographic reevaluation. We stratified pts based on those taking enzyme inducing antiepileptic drugs (EIAED; Group B) and those not taking EIAED (Group A) and conducted pharmacokinetic studies. Results: To date 32 pts (17 pts in Group A and 15 pts in Group B) have been accrued to the trial and 28 pts were evaluable for response. Treatment has been well tolerated with only one possible case of drug-related toxicity > grade 1 (Grade 2 thrombocytopenia). 11 pts have received more than 1 cycle of treatment (6 pts in Group A and 5 pts in Group B) and several pts have been stable on treatment for greater then 3 months and a number of other pts continue treatment with LY317615. Objective radiographic responses have been seen in 5 pts. Conclusion: LY317615 appears to have antitumoral activity against recurrent malignant gliomas. The trial continues to accrue additional pts and mature clinical and pharmacokinetic data will be presented at the meeting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co.