tbuckley/cabot-search huggingface dataset:
Efficacy of intrapleural administration of amrubicin, a novel anthracycline derivative, for disseminated pleural tumor model
Authors: M. Nakagawa, F. Tanaka, K. Takenaka, H. Wada
Journal: Journal of Clinical Oncology (2004)

2126 Background: Malignant pleural effusion caused by disseminated pleural tumors is a common and critical issue in patients with advanced malignancies. Pleurodesis is usually performed for the control, but it sometimes fails to control or cause some complications. In some clinical studies, intrapleural administration of chemotherapeutic agents such as doxorubicin was tested, but the efficacy has not been established. Recently, amrubicin (AMR), a novel anthracycline derivative, has been developed, and the present experimental study was conducted to examine the efficacy of intrapleural AMR administration in disseminated pleural-tumor models. Methods: Two human non-small cell carcinoma cell (NSCLC) lines (A549, adenocarcinoma; H1299, large cell carcinoma) and one pleural mesothelioma cell line (H211) were used. BALBc Nu/Nu mice were injected with 5,000,000 tumor cells into the pleural space. When disseminated pleural tumors were established, we started repeated intrapleural administration of AMR (5mg/kg/day, once a week for 8 weeks); the optimal schedule and dose, which caused no significant body weight-loss, was determined in preliminary experiments. Results: Repeated intrapleural administration of AMR significantly prolonged survivals in all three cell-line models (Table). In H211-disseminated model, the efficacy of intrapleural administration was also compared with that of intravenous administration, which revealed the superiority of intrapleural administration (MST, 97days vs 55days; p=0.074). Conclusions: Repeated intrapleural administration of AMR was effective in in vivo disseminated pleural tumor models, and we are now planning a phase I-II clinical study of repeated intrapleural administration of AMR. No significant financial relationships to disclose.
Weekly paclitaxel (P) combined with biweekly vinorelbine (V) in metastatic breast cancer (MBC): Final results of a clinical phase II study
Authors: T. Bouillet, P. Saintigny, E. Levy, J.-P. Spano, F. Morin, A. Pommeyrol, B. Brun, M. Bennamoun, J.-L. Breau, J.-F. Morère
Journal: Journal of Clinical Oncology (2004)

783 Background: In a previous clinical study (ASCO 2000 # 417), we demonstrated a therapeutic synergism of combined P and V two microtubule poisons with opposite mechanism of action. To optimize efficacy and safety we evaluated a weekly P and biweekly V schedule. Methods: Patients with MBC previously treated with anthracyclines received biweekly V 25 mg/m2 and weekly P 80 mg/m2, 8 weeks course, 2 weeks rest. Results: 20 patients (pts) entered the study, with the following characteristics: median age 64 (range 31–74); performance status 0 (12 pts 60%) and 1 (8 pts 40%); postmenopausal 15 (75%); oestrogen receptor negative 14 (70%); pts relapsing within 12 months after anthracyclin-based adjuvant therapy 5 (25%); 13 pts (65%) received one prior chemotherapy for MBC. A total of 189 weeks of treatment could be achieved, with an average of 9.5 weeks (range 1–16). No toxic death was observed. The most frequent adverse event was grade 2 (1 pt 5%), grade 3 (10 pts 50%) and grade 4 (4 pts 20%) neutropenia, including 5 (25%) febrile neutropenia. Haematological support with G-CSF concerned 12 pts (60%). One grade 4 thrombocytopenia was observed. Non haematological toxicity was uncommon: 4 pts (20%) and 1 pt (5%) experienced grade 1–2 and grade 3 peripheral neurotoxicity respectively; 1 pt (5%) experienced grade 4 nausea-vomiting. An objective response was observed in 10/18 evaluable pts (55.5%; 95% confidence interval=32–78) with 1 complete response and a stable disease was observed in 7/18 pts. The median progression-free survival was 174 days (range 12–440). Conclusions: With haematological support, this regimen is feasible in pts with anthracyclin-resistant MBC. Peripheral neurotoxicity is infrequent and manageable. Clinical benefit is promising. No significant financial relationships to disclose.
Incidence complications following sentinel lymph node biopsy or axillary lymph node dissection after breast cancer surgery.
Authors: Marcelo Adeodato Bello, Anke Bergmann, Ricardo Dias, Luiz Claudio Santos Thuler, Fabiana Tonellotto, Renata Reis Pinto, Erica Fabro
Journal: Journal of Clinical Oncology (2012)

97 Background: To reduce arm morbidity the sentinel lymph node biopsy was implemented in the breast cancer treatment. The aim of this study was to investigate the arm morbidity after sentinel lymph node biopsy or axillary lymph node dissection. Methods: This is a prospective cohort study of women who underwent surgical treatment of breast cancer at a single institution. Arm and shoulder morbidity were measured before, 1 and 6 months after the operation. Analyses were performed to compare morbidity between sentinel lymph node biopsy (SLND) and axillary lymph node dissection (ALND). This study obtained approval from the National Cancer Institute research and ethics committee. Results: Were included 203 patients and, during the study, 6 were excluded and there was 23 losses of follow-up. The average age of women was 58 years (DP=13). SLND was made in 31,6% with an average of 3 lymph nodes removed. Among those submitted to ALND, the average lymph node removed was 18 (p&lt;0.0001). After 45 days of surgery, the incidence of arm morbidity was: 23% of shoulder restriction (ALND 22%, SLND 1%, p&lt;0.001); 28% of axillar web syndrome (ALND 24%, SLND 4%, p&lt;0.001); 38% of seroma (ALND 32%, SLND 6%, p&lt;0.001); 5% of arm edema (ALND 4%, SLND 1%, p&lt;0.001). In the final evaluation occurred 6 months after the surgery, it was observed de following incidence: 4% of shoulder restriction (ALND 3%, SLND 1%, p=0.371); 18% of arm pain (ALND 12%, SLND 6%, p=0.460); 18% of axillar web syndrome (ALND 16%, SLND 2%, p&lt;0.002); 5% of arm edema (ALND 4%, SLND 1%, p=0.417). Conclusions: After 45 days of surgery, patients with SLND has less arm morbidity compared with patients submitted to ALND. After 6 months, it was observed less incidence of arm symptoms and only axillary web syndrome were more incident in patients with axillary dissection.
Abstract 16422: 4D Flow MRI Improves Assessment of Aortic and Pulmonary Peak Velocities in Patients With D-Transposition of Great Arteries Following Arterial Switch Operation
Authors: Kelly Jarvis, Susanne Schnell, Alex Barker, Marleen Vonder, Michael Rose, James Carr, Joshua D Robinson, Michael Markl, Cynthia Rigsby
Journal: Circulation (2014)

BACKGROUND: Pulmonary artery stenosis is the most common complication seen following the arterial switch operation (ASO) for D-transposition of the great arteries (DTGA). During follow-up, it is important to accurately detect peak velocity as an indicator of vessel narrowing. The purpose of this study was to compare peak velocity measurements by 4D flow MRI (4D flow) (with full volumetric coverage of aorta and pulmonary system) to those by standard 2D phase contrast MRI (2D PC) and Doppler echo. METHODS: 4D flow and 2D PC were performed in n=14 subjects (age = 12.4 ± 7.6, range = 1 to 25) with DTGA s/p ASO. 3D segmentation of the aorta (Ao) and pulmonary arteries (PAs) was performed to isolate 4D flow velocities for these vessels (Figure a). The location and value of peak systolic velocity was determined inside volumes of interest for the ascending aorta (AAO), main (MPA), right (RPA) and left pulmonary arteries (LPA). RPA and LPA 2D PC data were not available in one patient. Contemporary echo data were available in 11 patients (11 AAO, 8 MPA, 6 RPA, 5 LPA). RESULTS: Peak velocity measurements by 4D flow were significantly higher than 2D PC in all regions (AAO: 1.51±0.61m/s vs. 1.15±0.24m/s, p = 0.016; MPA: 2.08±1.11m/s vs. 1.44± 0.61m/s, p = 0.004; RPA: 2.19±0.65m/s vs. 1.79±0.81m/s, p = 0.027; LPA: 2.08±0.85m/s vs. 1.74±0.70m/s, p = 0.014). Regression results indicated strong relationships between 4D flow and 2D PC (AAO: R2 = 0.46, p = 0.008; MPA: R2 = 0.69, p = 0.0002; RPA: R2 =0.50, p = 0.007; LPA: R2 = 0.74, p = 0.0001) (Figure b). No significant difference was found between peak velocities measured by 4D flow and echo (AAO: p = 0.32, MPA: p = 0.24, RPA: p = 0.91, LPA: p = 0.36) or by 2D PC and echo (AAO: p = 0.49, MPA: p = 0.62, RPA: p = 0.35, LPA: p = 0.066). CONCLUSION: 4D flow outperformed 2D PC for detecting peak velocity in the Ao and PAs. No significant difference was found between peak velocities measured by 4D flow and echo. Further studies are warranted in a larger patient cohort to determine clinical impact.
Interleukin-8 (IL-8) serum levels and squamous cell cancer of the head and neck (SCCHN)
Authors: R. I. Haddad, A. S. Gokhale, L. Wirth, L. Weeks, J. Faucher, M. Hallar, L. A. Cavacini, M. R. Posner
Journal: Journal of Clinical Oncology (2004)

9716 Background: The pro-inflammatory factors, IL-8, VEGF, TGFα and PGE-2 are thought to be involved in SCCHN carcinogenesis, progression and metastasis. These cytokines act through pro-angiogenic and mitogenic effects. We hypothesize that elevated serum levels of these cytokines may predict stage or recurrence of SCCHN. In this study serum IL-8 was measured in patients with SCCHN, normal volunteers and healthy, treated patients. Methods: After informed consent, serum was obtained from normal volunteers (NV, n= 7), patients with no evidence of disease at least two years after treatment (NED, n= 5), patients with newly diagnosed, untreated SCCHN (ND, n= 14) and patients with recurrent disease (RD, n= 20). Active co-morbid illnesses, addictions, use of steroids or NSAIDS, or active anticancer therapy immediately prior to sampling were exclusion criteria. Serum IL-8 was measured by a commercially available ELISA. Patients and NV were matched for age and gender. Results: Serum IL-8 levels (pg/ml) are shown in the Table. 7/7 NV and 4/5 NED had levels < 20 pg/ml (mean of 13 and 15, respectively). In the ND group 2a/11 stage III/IV and 0/3 stage I/II disease had levels >20 (mean 18 and 14, respectively). In the RD group, 12/15 with metastatic disease (MD) and 4/5 with local regional recurrence (LRR) had IL-8 levels of > 20 (mean 44 and 29, respectively). Conclusions: Serum IL-8 levels are elevated in patients with RD SCCHN, with 80 %(16/20) having levels above 20 pg/ml. With this cutoff, sensitivity and specificity are 80% and 88% respectively. The pathophysiology of this finding is unknown. We continue to enroll patients on this study. It is possible that serum IL-8 can be used as a prognostic test in patients with ND or at risk for recurrence. IL-8 may also be a potential therapeutic target to control tumor growth and metastasis. No significant financial relationships to disclose.
Differential protein kinase activity in ER-positive and ER-negative breast cancer
Authors: R. Ruijtenbeek, A. Umar, L. van Houten, R. Hilhorst, J. A. Foekens, R. de Wijn, J. W. Martens
Journal: Journal of Clinical Oncology (2009)

e22142 Background: Specific protein tyrosine kinases (PTKs) promote cancer progression and are potential drug targets. The presence of the estrogen receptor (ER) is an important criterion in deciding on treatment of patients with breast cancer. Since PTKs can affect the tumors' receptor function, we investigated in our first proof-of-principle study whether it is possible to discriminate ER-positive (ER+) from ER-negative (ER-) tumors based on PTK activity using microarrays containing many PTK peptide substrates. Methods: Cryosections of 12 ER+ and 12 ER- breast tumors were lysed in the presence of appropriate protease and phosphatase inhibitors. The protein kinase activity in the lysates was monitored in vitro using PamChip peptide microarrays, which comprise of 253 PTK peptide substrates derived from known human phosphorylation sites. Peptide phosphorylation through active kinases can be monitored in samples in real time, using a fluorescently labeled phospho-tyrosine specific antibody. Results: Phosphorylation activity profiles were determined in quadruplicate using multiple independent sample preparations. Using ANOVA analysis, out of 253 peptides, several peptides with a different phosphorylation signal in ER+ and ER- samples were found: 22 with p &lt; 0.02 including VEGFR1, 2 and 3 and ADAM9. Multivariate unsupervised analysis using Principle Component Analysis showed a clustering of ER+ samples vs. ER- samples. Predictive analysis was performed using Partial-Least Squares Discriminant Analysis without explicit feature selection. The prediction error obtained from within experiment cross validation was typically in the range 10–20%. The error rate for between experiment prediction was 20%. An average predictive profile was constructed in which peptides with a relatively large weight were included, e.g. ADAM9 and BCAR1. Conclusions: Using PamChip peptide microarrays we have shown that differences in protein kinase activity exist between ER+ and ER- breast tumors. Our in vitro assay is a promising tool to investigate the interplay between kinase and nuclear receptor mediated signaling, with potential relevance to patient selection for targeted therapies. No significant financial relationships to disclose.
Phase II study evaluating the efficacy and safety of CNTO328 in combination with dexamethasone for patients with relapsed/refractory multiple myeloma (MM)
Authors: P. M. Voorhees, R. F. Manges, P. Sonneveld, G. Somlo, S. Jagannath, S. Zweegman, M. Munteanu, J. T. Vermeulen, H. Xie, R. Z. Orlowski
Journal: Journal of Clinical Oncology (2008)

8593 Background: Interleukin-6 (IL-6) plays a role in MM cell proliferation, survival, and corticosteroid resistance. We therefore evaluated the efficacy and safety of CNTO328, a chimeric monoclonal antibody with high affinity for human IL-6, in combination with dexamethasone (Dex) for patients with relapsed/refractory MM. Methods: Single arm, phase II trial, target accrual 40 patients. Eligibility: relapsed/refractory MM, ≥2 prior lines of systemic therapy including bortezomib, creatinine clearance ≥20 ml/min, platelets ≥50,000/mm3, neutrophils ≥1000/mm3. Treatment Plan A: first 14 patients, CNTO328 6mg/kg IV on D1 and D15 of a 4-week cycle. Dex was added upon progression or if a partial response (PR) was not seen after 2 cycles (40mg daily on D1–4, 9–12, 17–20 for 4 cycles followed by D1–4 for subsequent cycles). Treatment Plan B: patients 15–40, concomitant CNTO328/Dex beginning with cycle 1, D1. Results: 14 patients were treated on Treatment Plan A. Median age 62 years, mean time since diagnosis 4.9 years. 12/14 had ≥4 prior lines of therapy. All patients received prior bortezomib- and corticosteroid-based therapy, 12/14 thalidomide, and 7/14 autologous stem cell transplantation. Median number of CNTO328 administrations was 12. Common adverse events (AEs) of any grade included thrombocytopenia 50%, neutropenia 40%, anemia 30%, edema 30%, and upper respiratory tract infections 30%. Grade 3/4 AEs included thrombocytopenia 30%, neutropenia 20%, and hyperglycemia 20%. No responses were observed with CNTO328 alone, but 5/14 patients had stable disease after 2 cycles. Dex was added to 10/14 patients, 5 of whom achieved a confirmed PR. Median time to progression for Dex- treated patients was 5.4 months (range 43 days to not yet reached, with 2 patients continuing on therapy for >12 cycles). C-Reactive Protein (CRP), a marker of IL-6 activity, decreased by ≥94% at its nadir in 12/13 patients (10/13 undetectable). Enrollment onto Treatment Plan B continues. Conclusions: CNTO328 was well tolerated alone and in combination with Dex in this ongoing study. Although CNTO328 did not decrease paraprotein levels, it lowered CRP and yielded encouraging preliminary responses when combined with Dex in heavily pretreated patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Centocor R&D, Inc., Ortho Biotech Oncology R&D, a unit of Centocor R&D, Inc. Centocor, Inc, Johnson & Johnson, Ortho Biotech Johnson & Johnson
3-day topotecan and carboplatin in first line treatment of optimally debulked ovarian cancer: A phase II trial
Authors: R. Estape, E. Estape
Journal: Journal of Clinical Oncology (2005)

5144 Background: Primary treatment of ovarian cancer has improved over the last 10 years, but overall 5-year survival is still poor. Initial in-vitro laboratory synergism studies have shown that the combination of carboplatin and topotecan is superior to the current standard of care.This study was undertaken to assess the toxicity and response of primary ovarian cancer to a combination of 3-day topotecan and 1-day carboplatin. Methods: Patients with primary stage III or IV optimally debulked, < 1 cm, ovarian or primary peritoneal cancer were treated with 3-day topotecan at 1 mg/m2 and carboplatin at AUC = 5, at 21 day intervals. Primary endpoint are objective response and toxicity with a planned accrual of 46 patients in 2 stages. Response will be defined by clinical exam, radiological exam and CA125 values. Results: Stage 1 accrual was completed in 2002 with a greater than 50% objective response and stage 2 was begun in 2004 due to a change in study site. Preliminary data shows 35 entered patients with 31 evaluable for response. The 35 patients have received a total of 185 courses of 3-day topotecan and carboplatin. All patients are evaluable for toxicity and 31 of 35 are evaluable for response with a median follow-up of 18 months. Twenty-eight of 31 patients have had a complete response for an overall response rate of 90.3%. Median time to recurrence has not been reached for the stage 1 patients. Hematologic toxicity is predominant with grade 3 or 4 neutropenia occurring in 66 of 185 courses (35%) but only 2 patients required delays. Colony stimulating factors were added for all patients having Grade 3 or 4 neutropenia or anemia. Grade 3 or 4 thrombocytopenia occurred in only 14 of 185 courses, with only 1 patient requiring platelet transfusion. Fatigue, alopecia and nausea were similar to other trials. Conclusions: These findings suggest that 3-day topotecan and carboplatin are well tolerated and are active in this early trial. Although the combination has some toxicity, it can be managed conservatively with supportive care and with few delays. Continued accrual and follow-up is planned on this trial. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
Changes in high FDG-avid tumor volumes during radiation therapy differ from that of CT gross tumor volumes in patients with non-small cell lung cancer
Authors: L. Zhao, R. K. Ten Haken, F. Kong
Journal: Journal of Clinical Oncology (2007)

18139 Background: To study whether changes in Fluorodeoxyglucose (FDG)-avid tumor volumes (V PET ) correlate with changes in CT gross tumor volumes (CTGTV) during the course of radiation therapy (RT). Methods: Patients with stage I-III non- small cell lung cancer (NSCLC) were prospectively enrolled in this pilot study and were treated with fractionated RT based therapy with or without chemotherapy. FDG-PET/CT scans were acquired within 2 weeks prior to RT (pre-RT), after 45 Gy of irradiation (during-RT), and 3 months after completion of RT (post-RT). The scans were co-registered within our treatment planning system using the CT portion of each scan. Fused CTGTVs were delineated for each CT dataset. Fused V PET s were auto-contoured using 20%, 30%, 40% and 50% of maximum FDG activities within the tumors as threshold (V PET20 , V PET30 , V PET40 , and V PET50 , respectively) for each PET dataset. Paired T test and linear correlation were used for statistic analysis with all P values obtained using a 2-tailed test. Results are reported as Mean ± StDev. Results: Fifteen patients were enrolled in this pilot study. Pre-RT CTGTVs averaged 130.3 ± 194.7 cm 3 and reduced to 91.7 ± 155.3 cm 3 3 months after RT (P = 0.027). A mean PET threshold of 20.0 ± 10.6% matched best with the CTGTVs pre-RT. For the during-RT PET scans, the best-matched threshold increased to 30.0 ± 10.2% (P &lt; 0.001). No significant correlation was found between changes of V PET and reduction of CTGTV during-RT. During-RT changes of higher FDG-avid V PET significantly correlated with the reduction of CTGTV Post-RT (P values were 0.735, 0.189, 0.022, and 0.029 for V PET20 , V PET30 , V PET40 , and V PET50 , respectively), but during-RT changes of CTGTV did not (P = 0.113). Conclusions: Changes of high FDG-avid tumor volumes during-RT differ in magnitude from CTGTV changes. High FDG-avid tumor volume changes (instead of CTGTV changes) during-RT are correlated with CTGTV changes Post-RT. Further study in a large number of patients is needed to verify these findings. No significant financial relationships to disclose.
Evaluation of a New Tool for Exploring Podocyte Biology
Authors: MARCUS J. MOELLER, IULIA A. KOVARI, LAWRENCE B. HOLZMAN
Journal: Journal of the American Society of Nephrology (2000)

Study of podocyte biology has been hampered by limitations in available experimental models that both recapitulate the in vivo phenotypes of this cell and can be readily and specifically manipulated at the molecular level. Transgenic manipulation of the podocyte represents one approach that might circumvent these limitations. The purpose of this study was to identify a promoter-enhancer that would direct the expression of transgenes in a podocyte-specific manner. The nephrin (Nphs1) promoter was considered a good candidate for this purpose, because nephrin was thought to be expressed exclusively in podocytes. Two independent BAC clones that contained the murine Nphs1 gene were identified. An 8.3-kb and a 5.4-kb fragment containing the 5' flanking promoter sequence were identified and characterized. Two constructs were generated by placing a bacterial lacZ reporter with a nuclear localization signal under the control of these two DNA fragments. Mice transgenic for both constructs were generated. Using a chemiluminescence assay, beta-galactosidase activity significantly above control was detected only in tissue homogenates of kidneys and brain of transgenic mice. In X-gal stained sections of transgenic adult kidneys, only podocyte nuclei expressed beta-galactosidase. In adult brain examined by tissue sectioning, beta-galactosidase activity was confined to a discrete area in the medulla. Identical patterns of beta-galactosidase expression were observed in multiple transgenic founders, suggesting that the expression pattern observed was independent of the site of transgene integration. The developmental expression of beta-galactosidase in transgenic embryos was also analyzed. Transgenes regulated by this promoter should be useful for studying the biology of gene products that regulate podocyte phenotype and function.